Genetics, the science of the future

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Brent

Gabriel

Adrián

Himanshu

Shivani Chandra

Monse Rodríguez

Antonio Carusillo

STAFF DIRECTORY Marco Cid Fabian Valdes Calleja Carolina Villanueva Ivette Venegas Victoria Arnauda Sandra Gomez Pavel Moreno Cesar Perez EDITORIAL GENERAL DIRECTOR MARKETING DIRECTOR EDITOR IN CHIEF
A. Cid
Marco
Warner
Minelli
Rubstein
Sehgal
EXECUTIVE DIRECTOR COMMERCIAL TRANSLATOR GRAPHIC DESIGN (ARTEMIS) DIRECTION FINANCE COLLABORATORS YEAR 5, NO. 13, 2024 THE SCIENCE OF THE FUTURE Amparo Tolosa Jesús Zurdo Itzae A. Gutiérrez Hurtado Siva Kumar Buddha Ana Villaseñor-Todd Jordi A. Jauset Blanca Peredo Rick Ruiz-Dana ADVERTISE YOUR COMPANY ON CLINICAL RESEARCH INSIDER ! sandra.gomez@droxhealth.com / (+1) 786 269 0937 CLINICAL RESEARCH INSIDER, year 5, no. 13, February-April 2024 is a quarterly publication edited by CRPS CLINICAL RESEARCH PROFESSIONAL SERVICES, LLC. Edited in 12550 Biscayne Blvd., Ste. 110, Miami, FL. 33181 USA. Contact telephone: (+1) 786 269 0937. https://clirinsider.com/. Responsible Editor: Carolina Villanueva Lopez, Reserva de Derechos al Uso Exclusivo: 04-2023-032109391800-102 granted by the Instituto Nacional del Derecho de Autor (National Institute of Copyright), ISSN: 2992-801X. Certificado de Licitud de Título y Contenido (Certificate of Title and Content): in process. Responsible for last update: Carolina Villanueva Lopez, e-mail: carolina.villanueva@ clirinsider.org. Contact telephone: (52) 33 24 55 21 89. WWW clirinsider.com COMMUNITY MANAGER Francisco Hernandez GRAPHIC DESIGN Vanessa Velazquez GRAPHIC DESIGN

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Recoding the Human Being: The Modification of the Impossible Carolina Villanueva

Pag.

LATEST NEWS

- Searching for the Mexican Genetic Map.

- Japanese Scientists Create Drug That Regenerates Teeth That Have Fallen Out.

- Gene-editing therapy that eliminates HIV in mice, now in monkeys.

- The Drug That Promises Effortless Muscle-Building.

- New ways to stop Alzheimer’s.

- Genome editing to successfully transplant pig kidney into a human.

- Presentation of the new Pangenome.

- UK Approves Innovative Gene Therapy.

- DNA origami nanocages to treat tumors.

- Researchers discover clues to treat cancer through the dark genome.

CLINICAL COSMOS

Pag. 30-32

Pharmacomicrobiomics: The Impact of the Microbiome on Drug Therapy Efficiency

Itzae Adonai Gutiérrez Hurtado, PhD

Pág. 52-53

Unveiling Advanced Diagnostics and AIDriven Precision for Early Liver Injury Detection

Dr. Siva Kumar Buddha

SCIENCE TODAY

Pag. 41-45

Health and Work-Life Balance: The Key to a Fulfilling Life

Dra. Ana Villaseñor-Todd

Pag. 34-38

The impact of music on dementias

50-51

EDITION INQUIRY

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CHIEF EXECUTIVE OFFICER

Marco Cid, MBA

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THE EXPERT’S OPINION

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A Significant Milestone for the Future of Gene Editing

Brent Warner

Pag. 13

Precision oncology: challenges and ways forward Gabriel Minelli

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CENTRAL RESEARCH

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When CRISPR meets Dark Genome: Epigenetic Editing Adrián Rubstein, PhD

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Pag. 24-28

Accelerated adoption of Genomics in Latin America Monse Rodríguez, M.C.

Genome Medicine: The Future is Now Antonio Carusillo, PhD

Pág. 46-49

First CRISPR therapy for a genetic disease approved Amparo Tolosa, PhD

Pág. 58-62

CAR-T Immunotherapies. Is it possible to design a more complex product?

Jesús Zurdo, PhD

Pag.

Jordi A. Jauset, PhD Top

If genetic engineering allowed you to modify your future children’s aesthetic traits, would you subject them to the process?

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63-64 GADGETS

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PERSONAS EN LA CIENCIA

Henrietta Lacks The HeLa Cell Controversy and Good Clinical Practices

Lic.-Ing. Blanca M. Peredo Vázquez

39-40

BUSINESS & DEVELOPMENT

- Novartis Enters a $100 Million Gene Therapy Deal with Voyager.

- $60 million agreement signed to combat familial neurological diseases.

- For $10 billion, AbbVie buys pharmaceutical company ImmunoGen.

- Bristol-Myers Squibb to pay $800 million advance to Chinese drugmaker.

- Vertex/CRISPR Values Sickle Cell Gene Therapy at $2.2 Million.

- Pfizer to buy Seagen for $43 billion for its cancer drugs.

- Bristol Myers to acquire brain drug developer Karuna for $14 billion.

- The Next Great Abyss of Pharmaceutical Patents; Key Stats.

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EDITORIAL
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5 Cell and Gene Therapy Companies TABLE OF CONTENTS 4

Being able to combat a wide variety of genetic disorders that were thought to be incurable and even detect abnormalities in the DNA of a human fetus for future correction is undoubtedly a motivation that has driven innovation and the development of gene therapies around the world. Nonetheless, it is a modern and ever-evolving science that deserves the entire industry’s attention.

In this sense, preventing disease before it occurs is the ideal of any health system; however, giving life to a new gene therapy implies a high degree of investment and research in the field, together with experience in manufacturing and analyzing this type of medical advances. Those who have advanced on the path of genetic modification to provide greater certainty face a complex field full of obstacles, from developing new processes and manufacturing innovative medicines to complying with meticulous regulations to deliver safety and efficacy data, all within pressing deadlines.

Recoding the Human Being: The Modification of the Impossible

“Gene editing is not only a scientific tool but also a mirror that reflects our ability to shape the future of humanity.”

All these efforts undoubtedly aim to improve the quality of human life. These advances represent a revolution in how we approach disease, attacking the genetic root of disorders and providing more precise and personalized solutions.

Drug discovery never stops; there is always more to explore and understand. There are currently patients with little or no treatment available for their condition, so it is essential to establish alliances with technology partners and contract development and manufacturing organizations to push science further by continuously innovating and optimizing to remain at the forefront of drug research and development.

Fortunately, each genetic modification is a small step toward a future where hereditary diseases are relics of the paast, and health is a choice rather than a destiny.

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Searching for the Mexican Genetic Map

Aiming to expand the genetic information of the Mexican population, Tec de Monterrey and the global company Regeneron Genetics Center entered into a collaboration agreement to work on the megaproject called oriGen, where samples will be collected from 10,000 Mexican individuals to carry out an analysis of the genetic characteristics for this population. According to those involved, the research looks to fill the still-existing knowledge gaps in genetic information; this will benefit humanity in both the short and long term, in addition to improving patient care through a genomic approach.

Source: enfarma.lat

Japanese Scientists Create Drug That Regenerates Teeth That Have Fallen Out

Gene-editing therapy that eliminates HIV in mice, now in monkeys

The drug has been successfully used in animal trials and will now be tested in humans.

A Japanese research team aims to revolutionize the world of dentistry by developing a drug that allows people to grow new teeth. To this end, they have developed a pioneering drug that has been highly successful in animals; by July 2024, it will advance to the human trials phase. It would be the beginning of the world’s first dental regeneration medicine. The team plans to have it ready for general use by 2030.

Source: ABC Ciencia

For the first time, researchers from Temple University and Bebrakase University who managed to eliminate the human immudeficiency virus in mice will test their successful approach combining antiretroviral therapy with CRISPR genome editing in primates. Although this approach will be limited to implementation in mice and now primates, the project could lay the groundwork for curing HIV in humans. In addition, the researchers in charge of the study mentioned that this approach is “simple and relatively inexpensive.”

Source: Temple Health

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LATEST NEWS

The Drug That Promises Effortless Muscle-Building

The so-called SLU-PP-332, developed by the University of Florida and St. Louis, is a drug designed to deceive the body; its objective is to make the muscles believe that they are exercising, which generates in the body the typical natural response to exercise with all the benefits that it generates, such as increased energy expenditure and a faster metabolization of fat.

The treatment is still under development and has not caused any serious side effects. The next step in its development as a drug candidate will be to improve its structure, ideally by making it available as a tablet rather than an injection. The drug would be tested for side effects in more animal models before leaping human trials.

Source: ABC

New ways to stop Alzheimer’s

A team of scientists has genetically modified the brains of mice to discover that the MEG3 gene induces neuronal destruction. The study involved introducing 100,000 human neurons into the rodents’ brains to simulate dementia. They observed how neurons die and managed to remedy this neuronal death with two oral drugs already used against leukemia and melanoma.

Although there are still no drugs that cure or help alleviate the symptoms of Alzheimer’s disease, this study shows a promising path in terms of preserving neuronal cells.

Source: infobae.com

Genome editing to successfully transplant pig kidney into a human

Scientists at New York University Langone Health Hospital have successfully performed a pig kidney transplant on a 57-yearold brain-dead patient, achieving the most tremendous adaptability success in the history of xenotransplantation. The process involved genetic modification of the porcine organ to prevent the recipient’s immune system from rejecting the new organ. Four pig genes incompatible with the human body were suppressed, and another six human genes were added, producing urine and purifying creatinine.

Although the research is in the experimental stage, this advance in xenotransplantation represents a potential alternative for treating end-stage renal failure, as well as the study of transplants of other organs.

Source: National Geographic

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LATEST NEWS

Presentation of the new Pangenome

The new map, which cost $3 billion, includes the complete genetic sequence of 47 individuals from different backgrounds. The project aims to continue adding data to the ‘map,’ so it is expected that by mid-2024, it will include genetic information from 350 people of diverse ethnic descent. The developers mention that this project will help better understand people’s identity, know which genetic material sequences make us different, and learn aspects of our evolution and the genetic diseases that affect us.

Source: El mundo, Ciencia y Salud

UK Approves Innovative Gene Therapy

The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has approved CASGEVY, the world’s first CRISPR gene-editing therapy. CASGEVY, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, aims to cure sickle cell anemia and transfusion-dependent β-thalassemia, which are genetic blood disorders. Casgevy is the first licensed drug to use the innovative gene-editing tool CRISPR, for which its inventors received the Nobel Prize in 2020. The FDA is expected to follow in the UK’s footsteps later.

Source: Cell & Gene Therapy News

DNA origami nanocages to treat tumors

Chinese researchers have developed DNA origami nanocages that release CRISPRCas9 only in the presence of specific tumor markers such as ATP or miRNA-21. This method ensures targeted gene editing directly within tumor cells, significantly reducing their growth. This innovative approach offers a precise and effective way to apply CRISPR to treat tumors, demonstrating its success in both living and laboratory models.

Source: CRISPR Medicine News

Researchers discover clues to treat cancer through the dark genome

A study by South Africa and Zambia researchers examined genetic and drug dependencies in human cancers, focusing on the “dark genome.” They found that dark genes have high mutation rates in certain cancers and are crucial to patients’ survival outcomes, similar to light genes. The research highlights the therapeutic potential of targeting the dark genome in cancer treatment by analyzing drug response and CRISPR-mediated gene inactivation.

Source: CRISPR Medicine News

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CHIEF EXECUTIVE OFFICER

Brent Warner

President, Gene Therapy at Poseida Therapeutics; Board Member, Cure Rare Disease.

A Significant Milestone for the Future of Gene Editing

Exciting news in the field of gene editing has emerged with the recent regulatory approvals of the groundbreaking gene-editing therapy, CASGEVY, in the U.S., European Union, Great Britain and beyond. Vertex Pharmaceuticals and CRISPR Therapeutics have collaborated to develop CASGEVY, or exagamglogene autotemcel (exa-cel), which aims to treat patients suffering from transfusion-dependent betathalassemia (TDT) and sickle cell disease (SCD).

This development marks a significant milestone for the future of gene editing and has generated considerable enthusiasm within the scientific and medical communities.

The approval of CASGEVY is an encouraging sign for the future of gene-editing therapies. It demonstrates that gene editing has progressed from a concept discussed in laboratories to a viable therapeutic approach with the potential to treat genetic diseases effectively. The achievement brings hope to patients and their families, who have been eagerly awaiting breakthroughs in gene editing.

Likewise, researchers, scientists, and clinicians are optimistic about the potential of CASGEVY and its ability to provide a new treatment option for patients with TDT and SCD. It serves as a testament to the power of collaboration and innovation in driving medical advancements.

The potential success of CASGEVY paves the way for the future development and acceptance of other gene-editing therapies. This achievement underscores the tremendous potential of gene editing to revolutionize the treatment landscape for a wide range of genetic disorders. With each milestone reached, the scientific community gains valuable insights and knowledge that will further enhance our understanding of gene editing technologies and their application in medicine.

Furthermore, the approval of CASGEVY helps outline the foundation for the regulatory pathway of future gene-editing therapies. As gene editing is still a newer field from reaching patients, this acceptance and a potential BLA approval will help provide a more precise roadmap for other companies and researchers working on similar treatments, streamlining the process and bringing us closer to a future where gene editing becomes a standard therapeutic approach.

In conclusion, this achievement showcases the remarkable progress made in the field and highlights the potential of gene editing to transform the lives of patients with genetic diseases. As we move forward, it is essential to continue supporting and investing in research and development efforts to unlock the full potential of gene editing technologies and bring hope to those who need it most. The future of gene editing has arrived, and it holds promise for a brighter and healthier future for all.

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USA THE EXPERT´S OPINION

Precision oncology: challenges and ways forward

Clinical Oncology has undergone a significant transformation in recent years, driven by technological advances and deep knowledge of the human genome.

The range of therapeutic options and clinical approaches has increased exponentially, offering new perspectives on cancer treatment. Along with this progress, however, comes the challenge of navigating a vast ocean of information—surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, transplants, and clinical trials. The options go further depending on the cancer and the type of tumor.

In this context, genomic testing emerges as an indispensable ally for clinical oncologists, providing valuable insights that support more assertive and efficient approaches.

Genomic testing, by analyzing the genetic profile of the patient and the tumor, allows a deeper understanding of the disease’s molecular characteristics. Combined with artificial intelligence technologies, this information is filtered and organized to offer a more specific view, facilitating decisionmaking.

Despite this framework, genetic testing alone can pose a challenge to the doctor. The dilemma between tissue testing or liquid biopsy, the right time to order the test, choosing between an expanded or specific panel, managing scarce materials, and interpreting the results are just a few of the questions that may arise.

Doctors must have support tools available to help them make the best decisions. After all, it’s not enough to have access; you need to know how to use it. In this sense, Grupo Fleury, a company with operations in Latin America through partnerships with other laboratories, doctors, etc., which aims to increase its footprint, has structured and made available a series of mechanisms to support oncologists and physicians in clinical practice and decision-making.

Like other areas of medicine, oncology tends to be increasingly precise and personalized. Networks of laboratories, pharmaceutical companies, suppliers, and other protagonists of this revolution must invest more and more in education, train their professionals, and structure fast and transparent contact channels. With more and more data, we will notably need intelligence to transform it into accurate information and benefits for the patient.

THE EXPERT’S OPINION
Director of Genomics Business at Grupo Fleury, a leading company in Latin America.
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Brazil

Adrian Rubstein

Argentina

Founder of Ax3.Bio, leading life sciences investment strategy and advisory company.

When CRISPR meets Dark Genome: Epigenetic Editing

Innovation happens fast in the Biotech industry, and technologies are being superseded for new technology even faster than before. When we are getting used to gene therapy, a new technology is getting attention and sizable investing: epigenetics.

What exactly is epigenetics?

Conrad Waddington coined the term “epigenetics” 81 years ago to describe phenotypic variation that

does not result from changes in genotype. Since then, significant progress has been made in understanding epigenetic mechanisms for gene control, including chromatin remodeling, DNA methylation at CpG islands, and post-translational modifications (such as methylation, acetylation, citrullination, and phosphorylation) of the N-terminal tails protruding from the core histones that package genomic DNA.

By orchestrating internal and environmental signaling cues into transcription independent of the

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Image of representation of chromatin structure, including histones and DNA, which remain available for epigenetic marks.

underlying genetic code, epigenetic regulatory mechanisms play a central role in nearly all cellular phenomena.

In general, the epigenome is a collection of heritable and nonheritable sequence independent biological molecules that converge to modulate chromatin structure, genome function, and gene expression patterns. Epigenomic regulation occurs through a complex interplay of proteins that bind to genomic DNA, biochemical modifications to DNA and histones, and structural changes that allow regulatory proteins to access DNA. Even though projects like ENCODE and the Roadmap Epigenomics Mapping Consortium have accelerated our understanding of epigenetic states in health and disease, the extent to which epigenetic alterations are drivers or consequences of disease is frequently unknown.

What is Epigenetic Editing?

The use of epigenetic enzymes to rebuild the localized epigenetic environment of an internal genomic region, usually to regulate transcription, is known as epigenetic editing. The use of nuclease-null deactivated (or dead) CRISPR/Cas systems (dCas)

to perturb non-coding nucleic acid elements, such as promoters, enhancers, and transcription factor binding motifs, as well as non-coding RNAs, to gain insights into their functional roles and the resulting epigenetic changes, has significantly accelerated epigenetic editing progress.

Many important factors still limit the development of epigenome editing, preventing its use in humans. Like conventional genome editing, the clinical utility of epigenome editing is limited by targeted delivery options, potential off-targeting, and efficacy. Many factors influence these issues, including the identity of the targeted tissue, the chromatin context of the therapeutic gene of interest, and the epigenome editor’s copy number.

So, who´s who in the epigenome editing game?

Chroma Medicine, Tune Therapeutics, Epic Bio, and Navega Therapeutics have raised a total of $ + 200 million in funding, joining Sangamo Therapeutics, Inc. and Encoded Therapeutics Inc. in the quest to make epigenome editing a clinical reality. These startups are primarily developing platforms based on catalytically

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inactive CRISPR systems linked to effector domains that regulate gene expression. Unlike currently marketed epigenetic cancer drugs, which act on a genome-wide scale and have dose-limiting toxicities, the specificity of epigenome editors promises to open up a wide range of new indications beyond oncology.

In a landscape crowded with small-molecule inhibitors, monoclonal antibodies, gene therapies, small interfering RNAs, antisense oligonucleotides, and traditional gene and base editing, epigenome editors’ ability to restore genes silenced in disease in a tunable and durable manner may prove to be a key therapeutic niche.

How far are we from getting this into the clinic?

Although the road ahead will be long and difficult, epigenome editing therapies will provide several novel therapeutic options. They show promise for monogenic diseases where the target genes outnumber the AAV gene therapy payload capacity, and a healthy endogenous gene can be upregulated or downregulated (depending on the condition). Perhaps the most compelling therapeutic applications are restoring gene expression in congenital diseases of genome imprinting (for example, DiGeorge syndrome), autosomal dominant diseases of haploinsufficiency, or downregulating cancer cell activity, conditions that traditional gene therapy may not be able to treat.

References

1. Quratulain Babar, Ayesha Saeed, Tanveer A. Tabish, Sabrina Pricl, Helen Townley, Nanasaheb Thorat, Novel epigenetic therapeutic strategies and targets in cancer, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,Volume1868, Issue 12, 2022. Retrieved from: https://doi.org/10.1016/j.bbadis.2022.166552.

2. Jennifer Khirallah, Maximilan Eimbinder, Yamin Li, Qiaobing Xu, Clinical progress in genome-editing technology and in vivo delivery techniques, Trends in Genetics, Volume 39, Issue 3, 2023, Pages 208-216. Retrieved from: https://doi.org/10.1016/j.tig.2022.12.001.

3. Fine-tuning epigenome editors. Nat Biotechnol 40, 281 (2022). Retrieved from: https://doi.org/10.1038/s41587-022-01270-w

4. Rittiner Joseph, Cumaran Mohanapriya, Malhotra Sahil, Kantor Boris, Therapeutic modulation of gene expression in the disease state: Treatment strategies and approaches for the development of next-generation of the epigenetic drugs. Frontiers in Bioengineering and Biotechnology. Retrieved from: https://www.frontiersin.org/ articles/10.3389/fbioe.2022.1035543

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5

Top Cell and Gene Therapy Companies

Courtesy of Himanshu Sehgal and Shivani Chandra of PharmaShots*

Standing tall and gradually paving its way through extensive research, Cell and Gene Therapy is a beacon of hope when treating rare and inherited diseases. Cell and gene therapy aims to prevent, treat, and potentially reduce the effects of the underlying cause of genetic diseases. Propelled by constant innovatory winds, the Cell and Gene therapy market is anticipated to grow by 20 percent year-over-year through 2025. With a total revenue of $52B, Merck & Co. was ranked the highest among the list of companies developing Cell & Gene therapy.

Total Revenue: $29.40B

Approved Therapy: Alofisel

Headquarters: Tokyo, Japan

An R&D-driven global biopharma company, Takeda is committed to discovering and delivering products across therapy areas. Takeda’s cell and gene therapy segment includes Alofisel. The MHLW approved Takeda to manufacture and commercialize Alofisel across Japan to treat patients with non-active or mildly active Luminal Crohn’s Disease.

Total Revenue: $46.16B

Approved Therapy: Breyanzi & Abecma

Headquarters: New York, United States

Bristol Myers Squibb (BMS) is a global biopharma company dedicated to developing and commercializing products targeting therapy areas, including Oncology, Cardiovascular, and Immunological Diseases.

BMS’s subsidiary, Celgene Corporation, is a pharmaceutical company primarily focusing on developing cancer treatment immunotherapies.

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Under its immunology cell therapy, Celgene has two approved therapies, Breyanzi and Abecma. Breyanzi was approved for the treatment of large B-cell lymphoma. Additionally, in collaboration with 2seventybio (a bluebird bio company), BMS also received approval for Abecma for the treatment of multiple myeloma.

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Total Revenue: $49.27B

Approved Therapy: Luxturna

Headquarters: Basel, Switzerland

Roche is a multination biopharma company that develops and commercializes products under therapy areas, including Oncology, Cardiovascular, and Immunological Diseases. Spark Therapeutics’ subsidiary discovers and delivers gene therapies for treating genetic disorders. Spark’s Luxturna was approved as a gene therapy for the treatment of Leber’s congenital amaurosis. Luxturna is developed using the active substance vortigene neparvovec. Earlier in Jan 2018, Spark Therapeutics entered into a licensing agreement with Novartis to develop and commercialize Luxturna in areas outside the US.

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Total Revenue: $50.54B

Approved Therapy: Zolgensma & Kymriah

Headquarters: Basel, Switzerland

Novartis is a global biopharma company that discovers, develops, and delivers pharma products to treat unmet medical conditions in therapy areas. Kymriah is the company’s first cell therapy approved for treating acute lymphocytic leukemia that utilizes the patient’s T cells to fight and kill cancer cells. Zolgensma, for its part, is Novartis’ approved gene therapy for treating spinal muscular atrophy (SMA). Zolgensma replaced the missing or defective SMN1 gene with a new copy of the gene in the patient’s Cell, thereby inhibiting disease progression.

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Total Revenue: $52B

Approved Therapy: Adstiladrin

Headquarters: New Jersey, United States

With focus areas extending to Cardiovascular, Diabetes, Oncology, Neurology, and Immunology, Merck is a multinational biopharma company that has also marked a significant spot amongst the companies developing Cell and Gene Therapies. Adstiladrin is the only medication the company has approved for cell and gene therapy. In Dec 2022, the US FDA approved Merck’s Adstiladrin for treating high-risk Bacillus CalmetteGuérin unresponsive non-muscle invasive bladder cancer.

Source:

*Based on annual reports, SEC filings, press releases and company websites. Presented in mid-2023 by PharmaShots.

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Monse

Accelerated adoption of Genomics in Latin America

The field of genomics has been steadily advancing in recent years, and the COVID-19 pandemic highlighted just how important this technology can be for understanding and combating infectious diseases. While the pandemic caused significant disruptions to healthcare systems and economies all over the world, it also provided a unique opportunity for countries in Latin America to reassess and accelerate their adoption of genomics [1].

Despite the challenges posed by limited resources and infrastructure, Latin American countries have made significant strides in incorporating genomics into their healthcare systems [2] and have established genomics research programs using this technology to improve clinical diagnostics.

In the post-pandemic world, Latin American countries are realizing the potential of tracking

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Genomics Specialist Latin America at Illumina

the origin and spread of infectious diseases and viruses, beyond SARS-CoV-2 and how the adoption of genomics in their healthcare systems may improve public health while having a better understanding of various diseaseslike cancer, rare/inherited diseases, and chronic diseases - and their impacts on diverse populations. However, there is still much work to be done in terms of expanding access and increasing funding for genomics research and implementation in Latin America.

According to the report Accelerating access to genomics for global health by the World Health Organization (WHO), “current uses and future applications of genomic technologies are critical for improving the health and livelihood of people in all parts of the world, regardless of

economic status”[3]. The report also highlights the need for coordinated efforts and strategic investments from governments, private entities, research funding agencies, and international organizations to fully realize this potential, and makes 15 recommendations “intended to accelerate the establishment of genomic technologies and to sustain their beneficial use”.

Furthermore, collaborations with global partners in genomics research can enhance knowledge sharing and help accelerate the adoption of new methods, protocols, and technologies creating opportunities for advancements in precision medicine and personalized therapies that will help to address the unique health needs of each individual in the region.[4]

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Thus, investing in genomics research infrastructure and training for healthcare professionals can go a long way towards improving public health in the region. By doing so, Latin America will join the global genomics community and contribute to a better understanding of diseases and their impacts worldwide while helping bridge existing health disparities in the region.

In conclusion, while the adoption of genomics in Latin America’s healthcare systems may be a challenging and time-consuming process, it is undoubtedly worthwhile.

References

[1] Leite, J.A., Vicari, A., Perez, E., Siqueira, M.M., Resende, P.C., Motta, F.D., Freitas, L., Fernández, J., Parra, B., Castillo, A.E., Fasce, R.A., Martinez Caballero, A.A., Gresh, L., Aldighieri, S., Gabastou, J.M., Franco, L.G., & Mendez-Rico, J. (2022). Implementation of a COVID-19 Genomic Surveillance Regional Network for Latin America and Caribbean region. PLoS ONE,17.

[2] Lucien, M.A., Forde, M.S., Isabel, M.R., Boissinot, M., & Isabel, S. (2022). Infectious diseases genomic surveillance capacity in the Caribbean: a retrospective analysis of SARS-CoV-2. LancetRegional Health -Americas,18.

[3] World Health Organization. (2023). Acelerar el acceso a la genómica en pro de la salud mundial: promoción, aplicación, colaboración y cuestiones éticas, jurídicas y sociales: informe del Consejo Científico de la OMS. Retrived from: https://iris.who.int/handle/10665/375818

[4] Norris, E.T., Wang, L., Conley, A.B., Rishishwar, L., Mariño-Ramírez, L., Valderrama-Aguirre, A., & Jordan, I.K. (2018). Genetic ancestry, admixture and health determinants in Latin America. BMC Genomics,19

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contacto@investigacionbiomedica.com.mx investigacionbiomedica.com.mx

Italy

PhD in Molecular Biology and Genome Engineer. Research and Development Scientist at Alia Therapeutics. Writer in CRISPR-Medicine News. Scientific Event Co-Organizer of the CRISPR Medicine Conference 2024.

Genome Medicine: The Future is Now

In the past, genetic-associated conditions have often been regarded as an unchangeable verdict. As something to deal with and live with forever. Most of the time the standard medical care can try to alleviate the symptoms associated with the disease, rather than completely curing it.

While this can in some cases prolong the life of the patient or even zero the life-threatening factor associated with the disease, it comes at the price of money, time, and the overall quality of the patient’s life who may have to take medications regularly and experience detrimental side effects [1].

Gene therapy: viral vectors delivering “the good news”

Genetic conditions derive from genes whose information they codify is either mistaken or completely absent due to mutations occurring at the DNA level. Like when a car component breaks down, the best solution could be to replace it. This is the main principle applied in Gene Therapy. Gene therapy’s approaches rely heavily on viral vector technology which leverages the components of viruses and their ability to infect cells. Particularly, technological advancement has made it possible to replace the

genetic information driving the virus-associated disease with the one codifying the healthy copy of a gene of interest (GOI).

Therefore, we can engineer specific types of viruses and turn them into a vector able to deliver to the cells of the patient the information required to effectively treat the condition. To date, most of the gene therapy clinical trials leverage viral vectors to deliver the curative gene. Many of them have been approved for the market for conditions for which no other cures would have been otherwise available like Spinal Muscular Atrophy (SMA) [2], Inherited Retinal Disease (IRD) [3], Hemophilia A [4] and more [5].

Genome editing joins gene therapy

Standard gene addition or gene replacement already represents a huge leap forward in treating genetic conditions. However, in the past decade, important scientific discoveries and great technological advancements have paved the way for the next era of therapeutics. These are the years of genome editing and precision medicine.

Genome editing employs a set of tools usually referred to as molecular scissors. However, due

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to the possibility of programming them at will, Designer Nucleases (DNs) is a more appropriate term. Molecular scissors or DNs is a general term that encompasses a set of enzymes sharing two main features:

1. They cut the DNA and therefore nucleases.

2. They can be programmed to bind to a defined DNA sequence and therefore they can be “designed”.

CRISPR and precision medicine

Genome editing enables us to act at the very root of a genetic condition, the DNA. While this could be wishful thinking or an overstatement, in recent years genome editing – and CRISPR in particular – has been deployed in different

human clinical trials, with some of there proving its worth as therapeutic.

Some notable examples are:

-CTX001 [6]: this clinical trial led by CRISPR Therapeutics aimed at treating Sickle-Cell Disease (SCD) and beta-Thalassemia. Both are caused by mutations in the gene involved in the formation of adult hemoglobin. Patients suffering from either of the conditions need to undergo frequent blood transfusions along with other medicaments to treat the symptoms. In this setting, CRISPR has been used to reactivate the expression of the fetal hemoglobin. Of the patients treated in the clinical trial, all are currently free from the symptoms of the disease, and they do not require blood transfusion any longer.

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-ATX001 [7]: this clinical trial led by Intellia Therapeutics used CRISPR to disrupt the expression of the TTR gene for the treatment of Transthyretin amyloidosis. This life-threatening condition results from the accumulation of a misfolded transthyretin (TTR) protein. Via using CRISPR/Cas9 they could ko the TTR gene, which resulted in a clearance of the relative toxic protein. Supported by such positive results, Intellia Therapeutics has been authorized to move the clinical trial to Phase III.

-VERVE-101 [8]: in this clinical trial Verve Therapeutics leverages one of the last iterations of CRISPR/Cas called Base editor that instead of simply cutting the DNA, it can change single DNA bases. By using Base editor Verve aims to abrogate the expression of the PCSK9 gene that is involved in the accumulation of LDL (low-density lipoprotein) cholesterol whose high levels are the leading cause of stroke and heart disease. Currently, Verve Therapeutics is receiving approval from FDA to conduct a first clinical trial in USA.

The potential of CRISPR in genome editing applications extends beyond genetic conditions. In fact, CRISPR is being currently applied also and not only to:

-Treatment of infectious diseases: EBT-01 [9]: this is one of the most recent clinical trials using CRISPR/Cas. The Excision Biotherapeutics is testing in Phase I clinical trial CRISPR/Cas to eradicate the viral genome of the HIV virus integrated within the human DNA. To do this it leverages the programmability of CRISPR to identify the viral sequences and to excise them from the human genome by cutting at the two sides of it. The Phase I trial focused on proving the safety of the practice and reported positive results and the next step will be to determine whether it can also represent a step forward toward the treatment of HIV infection and AIDS.

-Improvement of other Cancer Therapeutics [10]: CRISPR is being used as a tool to render the most advanced cancer therapies even more powerful. This is the case for CTX110 and BEAM101 which leverage CRISPR to improve the efficacy of

26 CENTRAL RESEARCH

Chimeric Antigen Receptor (CAR) T cells at fighting the tumor along with providing other properties that can make CAR T cells more powerful and versatile.

The future of genome editing and final remarks

Genome editing and CRISPR/Cas technology hold great promise for the development of new and more powerful therapeutics. While being relatively new to Designer Nucleases’ toolbox, CRISPR/Cas has already proved itself in human applications, with several clinical trials being run as we speak [11].

As we delve into the exciting era of genome medicine, it’s evident that genetic conditions

are no longer an unchangeable verdict. Thanks to groundbreaking advances in gene therapy, genome editing, and, notably, CRISPR technology, we are witnessing the dawn of a new age in precision medicine. While these innovations have already made significant strides in treating various genetic conditions, however, we must continue to research and refine the CRISPR system, working to enhance its accuracy and safety to expand its applications even further.

Every technology comes with potential sideeffects, in case of genome editing the possibility of introducing undesired and unwanted genetic modification elsewhere in the human genome is a constant threat.

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Therefore, enhancing the precision and safety of CRISPR technology is a paramount objective. Scientists are continually working towards refining the specificity of CRISPR systems to minimize unintended alterations in the genome, ensuring that treatments are not only effective but also safe for patients.

As we look ahead to the future of genome medicine, it’s essential to emphasize the importance of ongoing research and development in CRISPR technology. By focusing on improving precision, reducing off-target effects, and ensuring the utmost safety, we can unlock even more potential for CRISPR in treating a wider range of genetic conditions and diseases. The future of medicine is indeed now, but by continuously refining our tools and techniques, we can make it brighter and more promising for patients worldwide.

References

[1] Baldessarini, R., Tondo, L., 17 April 2019. Effects of Treatment Discontinuation in Clinical Psychopharmacology. Psychother Psychosom; 88 (2). PP. 65–70. Retrieved from: https://doi.org/10.1159/000497334

[2] Zolgensma, La única terapia génica que detiene la progresión de la AME. Last modification: October 2023. Retrieved from https://www.zolgensma.com

[3] Luxturna. Last modification: 2022. Retrieved from: https://luxturna.com

[4] Advate. Last modification: 2022. Retrieved from: https://www.advate.com

[5] Shchaslyvyi, A.Y., Antonenko, S.V., Tesliuk, M.G. y Telegeev, G.D. (2023). Current State of Human Gene Therapy: Approved Products and Vectors. Pharmaceuticals, 16. Retrieved from: https://doi.org/10.3390/ph16101416

[6] Altshuler, D., Chen Y., Corbacioglu, S., De la Fuente, et al. ( 21 enero, 2021). CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. The New England JournalofMedicine(NEJM), 384. PP. 252-260. Retrieved from: https://www.nejm.org/doi/ full/10.1056/NEJMoa2031054

[7] Amaral, A., Boyd, A. P., Cehelsky, J. E., et al. (August 5, 2021), CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis, TheNewEnglandJournalofMedicine (NEJM), 385. PP. 493-502. Retrieved from: https://www.nejm.org/doi/full/10.1056/ NEJMoa2107454

[8] Verve Therapeutics. Last modification: Retrieved from: https://www. vervetx.com/our-programs/verve-101-102

[9] B10Space. (October 25, 2023). Excision BioTherapeutics Presents Positive Interim Clinical Data from Ongoing Phase 1/2 Trial of EBT-101 for the Treatment of HIV at ESGCT 30th Annual Congress. Retrieved from: https://www.biospace.com/article/ releases/excision-biotherapeutics-presents-positive-interim-clinical-data-fromongoing-phase-1-2-trial-of-ebt-101-for-the-treatment-of-hiv-at-esgct-30th-annualcongress/

[10] Razeghian, E., Nasution, M.K.M., Rahman, H.S. et al. (2021). A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies. Stem Cell Res Ther 12, 428. Retrieved from: https://stemcellres.biomedcentral.com/articles/10.1186/ s13287-021-02510-7

[11] CRISPR News Medicine. CRISPR Clinical Trials. Retrieved from: https:// crisprmedicinenews.com/clinical-trials/

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Itzae Adonai Gutierrez Hurtado, PhD

Professor and researcher at the Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara; PhD

Pharmacomicrobiomics: The Impact of the Microbiome on Drug Therapy Efficiency

The variability in individuals’ response to medications is a serious issue impacting patient health and generating substantial burdens in both clinical and financial realms. This diversity in response to a drug is caused by several factors, such as the simultaneous use of multiple medications, the patient’s health condition, concurrent intake of food and medications, consumption of substances like alcohol or herbs, and the unique genetics of each individual, the latter recently termed pharmacogenetics (1).

In addition to the previously mentioned factors, it has recently been proposed that the microorganisms comprising the microbiome could also modify drug responses. As a result, the concept of pharmacomicrobiomics has emerged to describe the microbiome’s effects on drug absorption, activity, and toxicity. Within pharmacomicrobiomics, terms such as toxicomicrobiomics and pharmacoecology have been introduced. The former refers to the study of how microbiome variations affect

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the metabolism and modify the toxicity of xenobiotics, including drugs. Meanwhile, the latter term is used to conceptualize changes in microbial taxa or specific functions of the microbiome resulting from the administration of a drug with either microbicidal or promicrobial activity (2).

Although pharmacomicrobiomics focuses on the microbiome, the set of organisms that share a symbiotic relationship with humans, by studying their genome and their interaction with the host genome, most studies in this field have focused solely on the gut microbiota (2,3). This trend is not surprising, considering that about 90% of medicines consumed worldwide are administered orally and that the gut microbiota exhibits the greatest diversity among microbiota in the human body (4,5).

Currently, it’s been proposed that the intestinal microbiota significantly influences the proces-

ses of drug absorption, distribution, metabolism, excretion, and potential toxic effects, primarily through two fundamental mechanisms: drug accumulation and metabolism by the microbiota. Accumulation involves bacteria’s capability to store drugs within their cells without altering their chemical structure, resulting in two outcomes: a reduction in drug availability and changes in the microbial community’s composition. Regarding drug metabolism, intestinal microorganisms have been observed to modify drugs through processes such as oxidation, reduction, acetylation, deamination, hydrolysis, among others (6,7).

Despite a remarkable increase in the number of publications on pharmacomicrobiomics in recent years, understanding of the relationship between the microbiome and the host remains limited. A suggestive 2018 study compares microbiome research to the growth of a child, indicating that it is transitioning from infan-

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cy to learning to walk, but has yet to mature to fully understand its environment (8). Throughout history, humans have maintained an intimate relationship with the microbial world. Many microorganisms operate in symbiosis and are essential for human health and well-being. The study of this relationship between microorganisms and humans has sparked significant interest within the scientific community, showcasing a promising field for exploration.

In conclusion, the variability in drug response poses a complex challenge. Pharmacomicrobiomics stands out as a promising field, especially in exploring the intestinal microbiota and its critical processes of drug accumulation and metabolism. Despite the growing research interest, our understanding of the relationship between the microbiome and the host remains limited. Nevertheless, this field presents vast opportunities for future research and groundbreaking discoveries.

References

[1] S. Rai, G., J. Rozario, C. (2023). Mechanisms of drug interactions II: pharmacokinetics and pharmacodynamics. Anaesthesia & Intensive Care Medicine (4):217–20.

[2] Torres C. N., Martínez, L. E., Torres, C, N., López, Q. A., Moreno, O. J., González, M. A.,etal. (2023). Pharmacomicrobiomics and Drug–Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy. Int J Mol Sci. 24(23):17100.

[3] Perez N., B., Dorsen C., Squires, A. (2020) Dysbiosis of the Gut Microbiome: A Concept Analysis. Journal ofHolistic Nursing 38(2):223–32.

[4] Peretti S, Torracchi S, Russo E, Bonomi F, Fiorentini E, Aoufy K El, et al. (2022). The Yin-Yang Pharmacomicrobiomics on Treatment Response in Inflammatory Arthritides: ANarrative Review. Genes (Basel);14(1):89.

[5] Alqahtani, M. S., Kazi, M., Alsenaidy, M. A., Ahmad, M. Z. (2021). Advances in Oral Drug Delivery. Front Pharmacol; 12.

[6] Jourova, L., Anzenbacher, P., Anzenbacherova, E. (2016). Human gut microbiota plays a role in the metabolism of drugs. Biomedical Papers; 160(3):317–26.

[7] Klünemann, M., Andrejev, S., Blasche, S., Mateus, A., Phapale, P., Devendran, S., et al. (2021) Bioaccumulation of therapeutic drugs by human gut bacteria. Nature; 597(7877):533–8.

[8] Staley, C., Kaiser, T., Khoruts, A. (2018). Clinician Guide to Microbiome Testing. Dig Dis Sci.; 63(12):3167–77.

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Jordi A. Jauset, PhD

Doctor of Communication, engineer, and musician; Coordinator of the Music and Neuroscience study group of the Catalan Academy of Music; Scientific communicator. www.jordijauset.es

The impact of music on dementias

Dementia, defined as an impairment of cognitive functions that interferes with autonomy or independence in daily activities, is one of the most common causes of disability and dependence in adults. According to the World Alzheimer’s Report (2022), more than 78 million people worldwide will have dementia by 2030 and the number is expected to reach 139 million by 2050.

Although there are different types of dementias, with heterogeneous clinical manifestations and neuropathological characteristics, all of them cause interruptions in neuronal communication (causing cell death in different brain areas) due to the abnormal accumulation of proteins [1], both intra- and extracellular.

It’s estimated that between 60%-80% of all cases of dementia, the one diagnosed as Alzheimer’s disease (AD) is the most common in adults, causing a progressive deterioration of memory and a loss of functional autonomy.

In young people [2], the most frequent causes of dementia onset, and with a relatively high prevalence, are those produced by frontotemporal area degeneration (FTLD), and different variants may occur:

Behavioral (bvFTD), with abrupt changes in behavior and personality.

Linguistic (primary progressive aphasia PPA with progressive loss of semantic knowledge svPPA, and the non-fluent variant, nfvPPA, similar to Broca’s).

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Despite research efforts, there are still no medical solutions to cure dementia, but there are treatments that can reduce the progression of symptoms, albeit with time limits. One of them is through music therapy.

Let us remember, however, that properly used music, even taking into account its limitations, can also be an effective tool for the prevention of dementia, contributing to increase cognitive reserve and delaying the onset of symptoms due to the cognitive resources it demands and the neuroplastic activation it involves. Several lines of evidence suggest that lifelong musical activities, such as playing a musical instrument or dancing, are associated with a reduced risk of developing dementia [3].

The following are the findings of various studies regarding different affectations in people with Alzheimer’s dementia (AD).

Impairment of musical perception

There are contradictory results in relation to the affectation of the different brain circuits or areas involved in musical perception [4]. Thus, in pitch and timbre discrimination tasks, some studies conclude that there are no differences with healthy controls [5], and others that Alzheimer’s patients have a lower performance. In short, it is observed that deficiencies in music perception vary according to the different clinical syndromes and could depend, at least partially, on the impairment of other cognitive functions, such as working memory or executive functions.

Memory impairment

One of the cognitive functions essential for maintaining memory is attention, which is often easily impaired after a brain injury.

We know that different types of memory can be differentiated based on the use of distinct neural networks. Thus, procedural or implicit memory (recall of skills, such as riding a bicycle or playing a musical instrument [6]) or episodic or explicit memory (recall of personal experiences) do not share exactly the same brain areas. Implicit recall mainly involves the basal ganglia, the cerebellum, the premotor area and the anterior cingulate. In the explicit, the hippocampus, the prefrontal area and the temporal lobe.

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SCIENCE TODAY

In fact, although AD is, by definition, a progressive memory impairment, impairment differs according to the type of memory. Episodic or explicit memory is the first to be affected, but procedural or implicit memory remains relatively preserved even in the most advanced stages of the disease. Similarly, musical memory usually remains intact and therefore, the person affected by AD can sing and remember a song learned during childhood, but has forgotten the names of family members.

Autobiographical evocation

Music has also been appreciated for its ability to evoke autobiographical memories in people with dementia. Thus, it has been shown that patients with AD retrieve as many autobiographical memories as healthy people in response to music [7], even more than memories retrieved after viewing photographs.

By accessing, through music (knowing their musical history directly or through their friends or relatives), to certain important moments of

their lives, gratifying experiences that improve their quality of life are achieved. The purpose pursued in these cases, through music therapy, is the activation of memories and associations, the improvement of the mood and facilitate the person to interact with the environment.

Such autobiographical memories evoked by music are not found in patients with bvFTD, possibly due to degeneration of medial frontal regions that are involved in autobiographical memory.

Affect on musical learning

It has been shown that dementia does not entirely prevent affected individuals from learning music, even in the presence of severe episodic memory impairment. Cowles et al. (2003) described a violinist with AD who could learn new musical works despite her extremely pervasive deficit in anterograde memory [6]. Similar results were also found in a 91-year-old non-musician with severe AD, yet she was able to successfully learn [9] a new piece of music.

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The therapeutic effects of music

The therapeutic effects of music, observed in cases of dementia, can be attributed to various reasons. First, some musical functions remain preserved in dementia patients despite their progressive cognitive decline. In fact, the neurodegenerative process generally affects some regions of the brain while others remain relatively intact for longer periods, allowing music therapists to act on and strengthen residual cognitive abilities. Second, other benefits may arise from the nature of music per se, given its ability to affect cognition as well as mood.

As exemplified in a recent model [10], active and passive activities with music engage numerous brain functions and regions simultaneously, which promotes neural plasticity. In addition,

the emotional connotation of music plays an important role in the efficacy of music therapy, as certain melodies can elicit positive mood states and provide the key to accessing meaningful autobiographical memories, as cited above. Music has a strong personal meaning (musical history) and helps people regain a sense of self.

The implementation of therapeutic protocols taking into account these potentialities offers encouraging results in cognition, attention and verbal fluency. For example, through 10 weekly sessions of music listening or singing, in patients with early dementia (diagnoses were not specified) stable or improved performance [11] was obtained in global cognition, attention and executive functions compared to standard attention. However, such positive consequences on cognition were not found in more advanced stages of dementia.

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In summary, several studies, both individual and group, show that even in the presence of cognitive and music processing deficits, some musical functions can be preserved in advanced stages of the disease. Furthermore, music may be beneficial in managing psychological, cognitive and behavioral symptoms in patients with dementia. Considering that these results need

References

to be extended and replicated, music therapy can be considered a promising tool to delay the symptoms of cognitive impairment and improve the quality of life of patients in a relatively easy and cost-effective way.

[1] Elahi, F. y Miller, B. A (2017). Clinicopathological approach to the diagnosis of dementia. NatRevNeurol13, PP. 457–476, Retrieved from: https://www.nature.com/articles/ nrneurol.2017.96

[2] Drapeau, J., Gosselin, N., Gagnon, L., Peretz, I. and Lorrain, D. (2009), Emotional Recognition from Face, Voice, and Music in Dementia of the Alzheimer Type. Annals of the NewYorkAcademyofSciences, 1169: 342-345. Retrieved from: https://doi.org/10.1111/j.1749-6632.2009.04768.x

[3] Verghese, J., Lipton, R. B., Katz, M. J., Hall, C. B., Derby, C. A., Kuslansky, G., Ambrose, A. F., Sliwinski, M., Buschke, H.,(2003). Leisure Activities and the Risk of Dementia in the Elderly, The New Journal of Medicine. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa022252

[4] Jauset-Berrocal, J.A. (2013). Cerebro y música, una pareja saludable. El Ejido (Almería): Círculo Rojo.

[5] Johnson, J., Chiung-Chih. Ch., Brambati, S., Migliaccio, R., Gorno-Tempini, M. L., Bruce M. L., Janata, P. (2011). Music Recognition in Frontotemporal Lobar Degeneration and Alzheimer Disease. Cognitive and Behavioral Neurology24(2). PP. 74-84. Retrieved from: https://journals.lww.com/cogbehavneurol/abstract/2011/06000/music_recognition_in_ frontotemporal_lobar.5.aspx

[6] Anne Cowles, William W. Beatty, Sara Jo Nixon, Lanna J. Lutz, Jason Paulk, Kayla Paulk & Elliott D. Ross. (2003). Musical Skill in Dementia: A Violinist Presumed to Have Alzheimer’s Disease Learns to Play a New Song. Neurocase, 9:6, PP. 493-503. Retrieved from: https://www.tandfonline.com/doi/abs/10.1076/neur.9.6.493.29378

[7] Cuddy, L.L., Sikka, R. & Vanstone, A. (2015), Preservation of musical memory and engagement in healthy aging and Alzheimer’s disease. Ann. N.Y. Acad. Sci. PP. 223-231. Retrieved from: https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.12617

[8] Baird, A. et al. (2018). ‘Characterization of Music and Photograph Evoked Autobiographical Memories in People with Alzheimer’s Disease’. Journal of Alzheimer’s Disease, vol. 66, no. 2. PP. 693-706. Retrieved from: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180627

[9] Baird, A., Umbach, H. & Forde W. (2017). A nonmusician with severe Alzheimer’s dementia learns a new song. Neurocase, 23:1. PP. 36-40. Retrieved from: https://www. tandfonline.com/doi/abs/10.1080/13554794.2017.1287278

[10] Brancatisano O, Baird A and Thompson WF. (2019). A ‘Music, Mind and Movement’ Program for People With Dementia: Initial Evidence of Improved Cognition. Front. Psychol. Retrieved from: https://www.frontiersin.org/articles/10.3389/fpsyg.2019.01435/full

[11] Särkämö, T., Tervaniemi, M., Laitinen, S., Numminen, A., Kurki, M., Johnson, J. and Pekka Rantanen, P., (2014). Cognitive, Emotional, and Social Benefits of Regular Musical Activities in Early Dementia: Randomized Controlled Study, The Gerontologist, Volume 54, Issue 4. PP. 634–650. Retrieved from: https://academic.oup.com/gerontologist/ article/54/4/634/650429?login=false

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Novartis Enters a $100 Million Gene Therapy Deal with

Voyager

Swiss drugmaker Novartis will pay biotech company Voyager about $100 million in cash up front, including $20 million in stock, in a deal worth as much as $1.2 billion. In return, Novartis will receive worldwide rights for experimental gene therapy for Huntington’s disease and a license to use the biotech’s gene therapy delivery tools to develop a treatment for spinal muscular atrophy, or SMA.

Source: BioPharma Dive

$60 million agreement signed to combat familial neurological diseases

Cure Genetics and Frametact Limited, a biotechnology company specializing in the research and development of drugs for neurological diseases, have signed a licensing and collaborative development agreement for a gene therapy capable of combating familial neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s disease. The development will be carried out through the VELP platform, patented by Cure Genetics, for which they will receive an initial payment of $60 million, in addition to royalties once the product is launched on the market.

Source: BioSpace.com

For $10 billion, AbbVie buys pharmaceutical company ImmunoGen

With a $10.1 billion investment, AbbVie acquires ImmunoGen due to its promising targeted cancer therapies. The company’s value tripled in 2023 because of its drug Elahere, which helped prolong the lives of ovarian cancer patients in a late-stage trial. The deal boosts its plans to enter the cancer drug market as its best-selling product, Humira, a treatment for rheumatoid arthritis, faces fierce competition in the United States. This transaction is expected to close in mid-2024.

Bristol-Myers Squibb to pay $800 million advance to Chinese drugmaker

Bristol Myers Squibb will pay $800 million upfront and up to $8.4 billion to a unit of drugmaker Sichuan Biokin to develop and commercialize one of its cancer treatments outside China. According to the developers, the drug has shown promise against a variety of solid tumors, including non-small cell lung cancer, cancer, and breast cancer. The treatment is currently in early-stage clinical trials.

Source: MarketScreener

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Vertex/CRISPR Values Sickle Cell Gene Therapy

at $2.2 Million

Vertex Pharmaceuticals and its partner CRISPR Therapeutics announced that their gene therapy for sickle cell anemia, Casgevy, would be available at a list price of $2.2 million in the United States. The biotechnology company Bluebird Bio mentioned that it has set a list price of 3.1 million dollars for its treatment, Lyfgenia, for this condition. The U.S. health regulator approved both therapies at the end of 2023.

Source: Reuters

Pfizer to buy Seagen for $43 billion for its cancer drugs

Pfizer agreed to pay $43 billion in a successful deal to acquire Seagen, a biotech company pioneering a new class of tumor-killing drug. The acquisition is the greatest Pfizer has attempted since buying Wyeth in 2009 and is the largest in the pharmaceutical industry by value since AbbVie’s $63 billion purchase of Allergan in 2019. The acquisition of Seagen gives Pfizer control of the best-selling lymphoma drug, Adcetris, and a portfolio of cancer treatments that has generated three new drug approvals over the past three years.

Source: BioPharma Dive

Bristol Myers to acquire brain drug developer Karuna for $14 billion

Bristol Myers Squibb has agreed to acquire Karuna Therapeutics for $14 billion, betting that the biotech company’s experimental schizophrenia drug will become one of the bestselling drugs. The acquisition gives Bristol Myers a well-known drug called “KarXT,” which is currently being reviewed by the FDA as a potential treatment for schizophrenia. The drug is a newer type of medication that doesn’t work like the treatments available for schizophrenia. It has already been successful in three mid- and late-stage tests and, if approved by regulators, could launch by the end of 2024.

Source: Forbes Mexico

The Next Great Abyss of Pharmaceutical Patents;

Key Stats

By 2030, patents on nearly 200 drugs will expire, and almost all major pharmaceutical companies will be affected. Essential medicines like Merck & Co.’s Keytruda, Regeneron’s Eylea, J&J’s Stellara, Eli Lilly’s Trulicity, and a trio of Bristol Myers Squibb blockbusters (Opdivo, Eliquis, and Revlimid) will lose exclusivity to their patents by the end of the decade. According to an analysis by Evaluate Pharma, the total value of the industry’s at-risk sales will rise this year to $44.4 billion, fall next year, and grow steadily again each year until peaking in 2029.

Source: Pharma Voice

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Dr. Ana Villaseñor-Todd

Scientist, doctor by profession and Mexican businesswoman noted for her studies in minimal hepatic encephalopathy, oxidative stress, quality of life and social cognition. Certified by the Pan American Health Organization (PAHO) as a facilitator of MhGap; CEO VICOMMA Group.

Health and Work-Life Balance: The Key to a Fulfilling Life

Gabriel Ponzanelli was one of the sculptors of the most beautiful memories of my childhood. The scene stays with me as if it were yesterday. However, the day my father took me to The Blue House and Frida Kahlo’s work, my insolence made me think that her art was overrated... That sense stayed with me for many years because by then, I was extremely excited by the asymmetrical structure of Fernando Romero, the great Soumaya, and the wonders of MoMa.

I always found someone else to admire in my brief studies of painting and art history. Then, one day, I came across “My Broken Column” in the strict sense of the expression; then I understood what it was all about: art does not reproduce what is visible but makes visible what is not always visible.

As Frida Kahlo would say, “I suffered two serious accidents in my life.” The first was when a speeding car crashed into my car as I was leaving work, fracturing the osteosynthesis material of my prosthetic spine. The second one happened at my job, being by far the worst. Like most scientists, I have had my days of political persecution while trying to seek immortality through my contributions; a slip in my workplace led me to the operating room for the first

time. I should have made it to safety back then. The Broken Column is a work where the artist portrays herself enclosed in a steel corset to support her spine. Her spine is depicted as an ancient pillar broken in several places, with many nails buried in her naked body. Suddenly, living with pain takes a back seat. The nails coming down the right side of

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SCIENCE TODAY

the blanket that covered her lower body, and the fissured landscape, dry and bare, became a symbol of pain and loneliness.

Some things stand out in a daily exercise of gratitude, such as preserving life, movement, family ties, or social ties. Still, the term “interfacelife-work” becomes increasingly complex because one is faced with what are known as invisible disabilities.

The term work-life interface refers to the relationship between the work and non-work environments. This umbrella term includes three

different facets: a) negative facet (i.e., conflict), (b) positive facet (i.e., enrichment), and c) integrative facet (i.e., balance). The first facet is the conflict between work and personal life that occurs when there is a perceived incompatibility between work and other areas of life. For example, work demands can interfere with family needs and vice versa. Both situations can negatively impact employee wellbeing and family functioning and impair employee job satisfaction and performance.

Therefore, the boundaries between work and family life are often blurred so that the behaviors and emotions of individuals from one realm can

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spill over into another. So, the overflow can be bidirectional. Most studies on the work-family interface focus on the negative spillovers between the two domains(2). A conflict perspective is adopted, which assumes that people in multiple roles often do not have enough time (i.e., timebased conflicts) to meet the demands of all roles (2).

Alternatively, they cannot meet the requirements of one role due to certain required behaviors (i.e., behavior-based conflicts) or tensions resulting from their participation in another role (i.e., tension-

based conflicts)(2). However, the positive effects between work and family, assuming the benefits of multiple roles, may outweigh the disadvantages(2). As such, resources produced in one function can improve the quality of experiences and outcomes in another function, leading to work-family enrichment(2). Enrichment can be conceptualized as a two-way construct. It can lead to workers experiencing greater well-being, lower turnover, increased work engagement, and better family functioning.

How work is organized and divided is closely related to stress, which can affect employees’ mental health. Highlighting a culture of wellbeing is essential; let us remember that NOM-035 arises from different national and international agreements and regulations that Mexico has ratified regarding labor justice, competitiveness, and trade.

Work-family balance is associated with high psychophysical health, reduced psychological distress and burnout, high family satisfaction and functioning, and positively associated with engagement. Resilience is a crucial point for people to experience greater well-being, less burnout, decreased psychological distress, and lower risk of depression. Positive work-related outcomes, such as increased job performance and lower staff turnover, are also likely to be reported.

During the Covid-19 pandemic, 17.3% to 75.3% of health professionals presented mental health problems. It has been four years since then, and I’m still seeing the ravages of well-being that have gone unaddressed. Returning to Kahlo’s expression, art can serve as a powerful resource to understand the natural course of diseases; she conveys to us the enormous difficulties that prevent her from working, being necessary to wear a steel corset for months. Like a mime, she makes the invisible visible; Certainly, the pain is not seen.

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Her surreal, profoundly, and even painfully personalized paintings fascinate art lovers worldwide. She captures in detail the physical, psychological, and social pain that would become the driving force and inspiration of many of her best works after the terrible bus accident she suffered in her youth and that, like me, left her with lifelong severe sequelae. To give an example, my husband

can officially say that his wife “has a couple of screws off” without me being able to refute it.

In all seriousness, my tragedy is neither a oneoff story nor the first nor the last. Compassion is a valuable personal resource, facilitating the relationship between affiliative humor and decreasing secondary traumatic stress. Affiliative

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humor implies self-acceptance. High levels of this style produce a tendency to say funny things, tell jokes, and amuse others to facilitate interpersonal relationships and reduce tensions.

Therefore, fostering compassionate skills could benefit an optimal professional quality of life. Unfortunately, today, within public institutions, the vast majority do not have a genuine interest in the well-being of employees or respect for the quality of life or human dignity, which is closely related to the gaps in mental health care. In terms of wages and gender, segregation, stigma, and misinformation are still prevalent. There is no culture of well-being.

Worryingly, mental illness globally accounts for 32% of years lived with a disability(1) and has significant impacts on workplaces. In particular, healthcare workers experience high rates of mental health problems, such as burnout, stress, and depression, due to deplorable working conditions, including excessive workloads, workplace violence, discrimination, and bullying, which also produces adverse effects on patients, as well as the happiness and well-being of those who remain on the

job(1). In high-income countries, organizational interventions include skills and knowledge development, leadership development, communication and team building, stress management, and workload and leisure time management.

All studies highlight the importance of employee engagement in developing and implementing the intervention. The literature review also supports the recognized need for more research on mental health and happiness in low- and middle-income countries and studies evaluating the longterm effects of mental health promotion in the workplace.(3)

Protective factors (resilience, perceived social support, and professional identification) and stressors (perceived stress and psychosocial risks in the workplace) influenced workplace well-being and perceived quality of life.

Frida Kahlo makes the days so brief that she incomparably teaches us that pain is nothing more than a symptom of our being alive.

References

[1] Timofeiov-Tudose IG., Măirean C. (2023) Workplace humor, compassion, and professional quality of life among medical staff. Eur J Psychotraumatol. 14(1):2158533. Recuperado desde: https://www.tandfonline.com/doi/full/10.1080/20008066.2022.2158533

[2] Bernuzzi, C., Sommovigo, V., & Setti, I. (2022). The role of resilience in the work-life interface: A systematic review. Work(Reading, Mass.),73(4), 1147–1165. Recuperado desde: https://doi.org/10.3233/WOR-205023

[3] Wong, KP, Lee, FCH, Teh, PL, Chan, AHS (2021). The Interplay of Socioecological Determinants of Work-Life Balance, Subjective Wellbeing and Employee Wellbeing. Int J Environ Res Public Health 18(9):4525. Recuperado desde: https://www.mdpi.com/1660-4601/18/9/4525

45 SCIENCE TODAY

CENTRAL RESEARCH

Scientific Director of Genotipia

First CRISPR therapy for a genetic disease approved

The UK drug regulatory agency has approved the first CRISPR genome-editing therapy for a genetic disease. It is Casgevy, a treatment for sickle cell disease and beta-thalassemia, developed by Vertex Pharmaceuticals and CRISPR Therapeutics.

The approval, just 11 years after the publication of the first article outlining the potential of CRISPR tools for genome editing, reflects the revolution this technique has brought about and the significant progress made in recent years.

“This is a world first and a significant moment for researchers, doctors, and above all, for people with sickle cell anemia and beta-thalassemia,” noted Josu de la Fuente, a professor and researcher at Imperial College London who participated in the clinical trials evaluating Casgevy. “These are hereditary blood disorders that have a profound impact on people’s lives. This approval provides a new option for patients who meet the necessary requirements and are awaiting innovative therapies.”

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SPAIN

“Both sickle cell anemia and beta-thalassemia are lifelong, painful diseases that, in some cases, can be fatal,” emphasized Julian Beach, Interim Executive Director of Quality and Access to Healthcare at the UK Medicines and Healthcare products Regulatory Agency. “I am pleased to announce that we have authorized an innova-

tive and pioneering gene-editing treatment called Casgevy, which, according to trials, restores the production of healthy hemoglobin in the majority of patients with sickle cell anemia and transfusion-dependent β-thalassemia, thus alleviating the symptoms of the disease.”

A therapy aimed at treating two diseases caused by alterations in the same gene

Casgevy, the commercial name for exagamglogene autotemcel or exa-cel, is indicated for the treatment of patients with sickle cell anemia or beta-thalassemia who meet certain established criteria.

Both diseases are blood disorders caused by mutations in the HBB gene that compromise the

production of hemoglobin. In the case of sickle cell anemia, the resulting defective hemoglobin causes red blood cells to take on an incorrect shape, leading to two main consequences. Firstly, these red blood cells die prematurely, which can result in anemia. Secondly, they can obstruct small blood vessels, causing issues in the distribution of blood to organs and episodes of pain.

In the case of beta-thalassemia, the production of hemoglobin is significantly reduced, leading to anemia and other associated complications.

47 CENTRAL RESEARCH
In sickle cell anemia, the resulting defective hemoglobin causes red blood cells to take on an incorrect shape, leading to their premature death and the potential obstruction of blood vessels.

Additionally, patients have a higher risk of developing abnormal blood clots. In severe cases, the disease requires regular transfusions, which come with their risks, such as increased iron in the blood, which can be harmful to certain organs and bodily functions.

What is Casgevy, the first CRISPR therapy?

Casgevy is an ex vivo cell therapy with modified cells to produce functional hemoglobin. The treatment involves obtaining hematopoietic stem cells (those that generate different types of blood cells) from patients, modifying them using CRISPR tools, amplifying them in the laboratory, and then reintroducing them back into the patients.

The genetic modification strategy leverages a highly relevant feature in both diseases: the responsible mutations affect the HBB gene, which encodes beta-globin, an essential component in adult hemoglobin. The key is that patients have another potential source of beta-globin intact: the gene that produces fetal beta-globin. The expression of this gene is automatically silenced shortly after birth, replaced by adult beta-globin. However, researchers have found a way to

maintain its expression in patients who do not produce adult beta-globin.

Regulation of the first CRISPR therapy and other open questions

Gasgevy, approved in the United Kingdom, is also under review by other regulatory agencies such as the European Medicines Agency, the United States Food and Drug Administration (FDA), and the Saudi Food and Drug Authority. In the U.S., the review for transfusion-dependent thalassemia is scheduled for March 30, 2024.

An open question remains regarding the price of the therapy. To establish the treatment’s cost, the responsible companies will take into account the research, development, and production costs of the drug, which must be prepared on a personalized basis for each patient. Currently, there is no official figure, although the Institute for Clinical and Economic Review estimates that the necessary price for the treatment to be cost-effective should range between 1.35 and 2 million dollars. Zynteglo, a similar therapy targeting beta-thalassemia without genetic editing, is priced at 2.8 million dollars in the U.S. In Europe, the initially set price was 1.8 million

CENTRAL RESEARCH
48

dollars. However, due to various production issues, the responsible company, Bluebird, decided to focus solely on the U.S. market.

In comparison to the potential cost of the therapy, the healthcare expenses for patients with sickle cell anemia or beta-thalassemia are high. For instance, it has been estimated that, up to the age of 64, the attributable medical expenditure for each patient with sickle cell anemia amounts to 1.7 million dollars (for insured patients). It remains to be seen whether the final price of the therapy enables all individuals who could benefit from it to receive the treatment. Ultimately, the question is whether the therapy, in addition to being effective, will be accessible.

The debut of CRISPR

Gasgevy’s approval marks a milestone for gene therapies. It is the first CRISPR-based therapy

Sources

approved for the treatment of a genetic disease. The recent development of CRISPR and derived genome editing systems represents a highly promising opportunity for numerous genetic diseases. Evidence of this is seen in the numerous clinical trials utilizing these technologies to correct genetic errors responsible for various diseases.

Vertex Pharmaceuticals and CRISPR Therapeutics, the latter co-founded by Emmanuelle Charpentier, jointly awarded the Nobel Prize in Chemistry in 2020 with Jennifer Doudna for the development of CRISPR as a method of genetic editing, have been involved in the development of Gasgevy. Currently, both companies have various therapies under investigation for diseases such as diabetes, Duchenne muscular dystrophy, or cardiovascular disease.

Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY™ (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Retrieved from: https://ir.crisprtx.com/news-releases/news-release-details/ vertex-and-crispr-therapeutics-announce-authorization-first

UK approves world-first gene-editing treatment for blood disorders. Retrieved from: https://www.imperial.ac.uk/news/249536/uk-approves-world-first-gene-editingtreatment-blood/

MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia. Retrieved from: https://www.gov.uk/government/ news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia

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50
51

CLINICAL COSMOS

Unveiling Advanced Diagnostics and AI-Driven Precision for Early Liver Injury Detection

Drug-Induced Liver Injury (DILI) poses a complex challenge, demanding advanced diagnostic strategies for timely intervention. Integrating key diagnostic parameters with cutting-edge technology is crucial, combining established guidelines with innovative tools to enhance precision diagnostics.

DILI encompasses a spectrum of hepatic disorders resulting from exposure to drugs or their metabolites, necessitating a comprehensive diagnostic approach for timely intervention.

Key diagnostic parameters include Hy’s Law, emphasizing elevated Alanine Aminotransferase

(ALT) and total bilirubin levels concurrently as potential indicators of severe DILI. An ALT exceeding three times the upper limit of normal (ULN) and total bilirubin surpassing two times ULN trigger heightened vigilance. Additionally, the Roussel Uclaf Causality Assessment Method (RUCUM) aids in distinguishing idiosyncratic from intrinsic DILI, with a score of 6 or higher serving as a red flag for severe hepatotoxicity.

The Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) emerges as a dynamic tool for organizing liver laboratory data. eDISH plots display peak serum ALT and total bilirubin levels for each subject, providing a visual perspective

52
Dr. Siva Kumar Buddha Director Pharmacovigilance, Head of Signal and Risk Managementat Indegene. India

CLINICAL COSMOS

of hepatotoxicity trends. This graphical representation enhances the understanding of liver safety data and facilitates early identification.

In clinical trials, FDA stopping rules are pivotal guidelines, dictating the cessation of drug investigations when specific criteria, such as those outlined in Hy’s Law, are met. Immediate action is crucial in the face of potential severe hepatotoxicity. DILI can result from various drug classes, including antibiotics, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs).

The mechanism involves drugs or their metabolites targeting different hepatic cells, leading to acute, subacute, or chronic hepatobiliary diseases. Technology plays a pivotal role in advancing DILI detection. Machine learning algorithms, trained on diverse datasets, can analyze eDISH plots alongside traditional markers, contributing to a more nuanced and comprehensive analysis of potential hepatotoxicity.

These algorithms can incorporate factors such as genetic predisposition, drug metabolism profiles, and patient-specific data. By leveraging artificial intelligence and machine learning, healthcare professionals gain a more sophisticated understanding of the complex interactions leading to DILI. Likewise, automated systems can trigger alerts when eDISH plots showcase a rapid rise in ALT and bilirubin levels, signaling potential severe DILI.

In conclusion, the integration of advanced diagnostics, key parameters, and technological tools, such as eDISH and machine learning algorithms, forms a robust strategy for early identification of DILI. This comprehensive approach, blending established guidelines with innovative techniques, enables healthcare professionals to leverage dynamic visualizations and algorithms, enhancing diagnostic accuracy, and enabling proactive interventions for improved patient outcomes.

53

Ask the Mousecid

1. I am interested to know if any food product showing health benefits must have the approval of COFEPRIS to be marketed. Thank you!

Brenda Martinez

Food Chemistry student at La Salle, Mexico City

A. Dear Brenda, thank you very much for your question, it is certainly a very interesting question. Let me tell you, for the registration of food it is not necessary to check its efficacy or safety, as is the case with medicines. However, I recommend that if at any time you plan to use efficacy to promote a product, it is important that you generate safety and efficacy data for it. A short research study can tell you a lot about it.

As such, this research project must be submitted to the Ethics, Research, and Biosafety Committees, before being sent to COFEPRIS. Remember that investing in research to know how effective the product is and to fully understand its safety profile translates into data that represents a competitive advantage in the market.

54 ASK THE MOUSECID

2. When a product in development presents too many problems to prove its effectiveness, what is considered better, to go ahead and modify it as necessary, even if a lot is invested, or is it better to discard it? At what point should the development of that product be given up?

Debanhi Garcia V.

Physician-Surgeon at UJED, Faculty of Health Sciences

A. Within product development, problems in demonstrating efficacy are the most common. In this case, I can recommend that you check if the questions were properly asked: what are we looking for to demonstrate efficacy? Are the biomarkers correct? Is the ADME system known? Do we know the needs of patients and build the efficacy we are looking for in them? Once you answer these questions, you’ll know if you’re looking for the right efficacy of your product.

If not, then I recommend that you modify the product to achieve the effectiveness you are looking for, it is best to understand where it is not working and change it.

Remember that you will have to prove the efficacy of your product to obtain the corresponding authorizations from the regulatory bodies where you are seeking approval. Finally, I think the time to give up on the product comes when you consider the size of the market you would like to reach, taking 1% of the market value, which is what you could potentially access. Once you make your financial runs by reviewing the costs of development, manufacturing, advertising, marketing, and sales processes, you’ll realize how far you can continue to look for product effectiveness.

Best of luck! We hope you tell us more in the future.

3. If a drug was validated in a foreign country for its manufacture and sale, can that same drug be sold in Mexico, for example, or must it also be submitted to COFEPRIS from the beginning?

Biochemistry Engineer, Miguel Perez

Instituto Tecnológico de Colima

A. Thank you, Miguel, for your question. Apart from being very good, it has an incredible complexity, I’ll tell you why. A drug approved in other countries may enter Mexico with documentation and approval for free sale in other countries. I recommend that you review which are the countries in which this type of strategy can be carried out, in any case, the submission of the documentation to COFEPRIS (DOSSIER) must be carried out.

On the other hand, if the country where it is manufactured is not a member of any international

treaty, the drug will be treated as a new registration with COFEPRIS and you will have to demonstrate its efficacy and safety profile through some research studies. In these cases, a lot depends on the type of medication and how much information you have about it.

There are regulatory agents in Mexico who can review the data you have and can guide you on your specific needs.

55 ASK THE MOUSECID

4. If it is proven that a medical product causes irreparable damage to health, can people sue the company that created it, even if it already has the approval of COFEPRIS and the government to sell it?

Fernanda Garcia

Graduated from Law school at the Faculty of Higher Studies Aragón UNAM

A. Hello, Fernanda, excellent question. Unfortunately, there are several documented cases in which a drug already approved for therapeutic use shows different safety profiles than those demonstrated in clinical trials, these can be severe or non-severe events for the patient’s health.

In these cases, although the pharmaceutical company tries very hard to obtain all the safety data in its clinical studies, it is often not enough. That is why some

phase IV studies or extended pharmacovigilance are excellent tools to continue collecting information about the drug once it is already on the market. I recommend that if you know of any adverse event not described on the label of the medication, you immediately notify the telephone numbers that are described on the label of the medication.

5. If a new pharmaceutical product proves to be as effective as an existing drug, can it be validated? If so, would it be worth launching it? Are there already cases of two drugs that are the same?

Benjamin Rodriguez

Metropolitan School of Biochemistry and Pharmacology

A. Thank you for the question, Benjamin. Let me tell you; If within our clinical trials, we demonstrate that there is the same efficacy between two products, I believe that the following questions should be answered: Is its form of administration less invasive? Is it cheaper? Do you need a lower dose for the same therapeutic effect? And how about your adverse events... are they minor? Beyond similar efficacy, we

must know what advantages our drug will have in the market compared to the competitor. There are many drugs with similar therapeutic effects but with different advantages, that’s where the decision to launch them on the market lies.

The answers we provide are based on the experience of 15 years of work in Pharmaceutical Research and Development; The comments expressed here are for personal purposes only and are not intended to be a substitute for professional consulting.

If you have any doubts or new questions, please write to preguntalealratoncid@clirinsider.org

56 ASK THE MOUSECID

PhD

United Kingdom

Novel Therapeutic Modalities: Where to innovate?

CAR-T Immunotherapies. Is it possible to design a more complex product?

In recent years, the use of CAR-T cell and related immunotherapies based on geneticallymanipulated immune cells have shown a remarkable success, not only in the treatment of haematological cancers, but also as an effective weapon against solid tumours. Despite the clinical efficacy shown by these treatments, there are still quite a few aspects that remain problematic, including the ‘persistence’ of the therapeutic effect, the incidence of severe undesirable effects (chiefly cytokine release syndrome), linked to a large degree to their own pharmacological effect, and finally the fact that most of these therapies are ‘autologous’, which complicates tremendously not

only the manufacturing, but also the eligibility of patients that could benefit from these treatments.

This has forced to put a great emphasis in designing the right therapeutic cell that can elicit an optimal clinical response in the patient, but also that can be manufactured with relative ease.

On one hand, requirements of large number of cells puts extraordinary demands and constraints in the manufacturing process, but also in the original biological material obtained from patient apheresis. After all, at this point in their clinical journey these patients are severely ill and therefore, not in an optimal condition to provide the required number and quality of immune cells to manufacture the final immunotherapy product.

So, clearly, in the future the design of these type of therapies will need to address the nature

58 CENTRAL RESEARCH Jesus
Cell, Gene Therapy & Bioproduction at Horizon Discovery
Zurdo,
Global Head

of the active ingredient or API itself, but also whether a ‘universal’ or off-the-shelf form might be better suited to treat these patients. Indeed, a potential avenue explored by a few developers is pursuing the development of ‘off-the-shelf’ immunotherapies that could be used to treat virtually any patient.

On the positive side, this could perhaps help reducing the substantial development and manufacturing costs associated with these innovative therapies, largely linked to the ‘one-patient one-batch’ conundrum and the use of still inadequate platforms to address effectively process integration and automa-tion in such therapies [1].

Furthermore, immediate availability would prevent disease progression that occurs in autologous therapies during the manufacturing process from apheresis to cell transduction, expansion, batch release and patient administration, which can take several weeks.

This raises a significant risk that patients could die before their treatment is ready. However, on the negative side, such a ‘universal’ approach for immunotherapy would require the development of cells that are recognised as ‘own’ by virtually any patient, or rather cells that will not trigger rejection (allorejection) or, even worse, graft vs host disease (GvHD) responses which could be potentially fatal to the patient [2].

the product. Several other alternatives are being actively developed, for example CAR-NK cells, that maintain their efficacy against the cancer cells, whilst reducing the incidence of GvHD and allorejection [3].

Moving away from the ‘active ingredient’ itself, the process of manufacturing this type of therapeutics could not be more complex. It is in fact ‘a process within a process within a process’, even if we leave aside for a moment the constraints imposed by factors such as patient personalisation, perishability of product, and complex demands in terms of chain of custody. There are indeed very complex manufacturing processes and supply chains in other industries (automotive, aeronautics, electronics, even in food), but they succeed by relying on a tight control over the design specifications of the final product.

This means, successfully controlling the quality of components and assembly / production of the final product within a very narrow range of set specifications, and by designing compatibility and interoperability of components applicable to a multitude of product configurations.

Unfortunately, none of this is present in the design and manufacture of this type of therapeutics (and perhaps in the pharmaceutical industry as a whole).

Some of these risks can be minimised by engineering immune cells by gene editing technologies to eliminate the expression of T-cell receptors (TCRs) or human leukocyte antigens (HLA) / histocompatibility antigens in

Nucleic acid therapeutics. Delivery remains a key challenge

One of the many attractive aspects of nucleic acid therapeutics is the promise of a relative simplicity

59 CENTRAL RESEARCH

of manufacture compared to other modalities, such as proteins. In fact, some have suggested that nucleic acids (particularly mRNA vaccines) could deliver the promise of true personalised medicine. However, several challenges remain for such an ‘ideal’ manufacturing process.

One of the problems with RNA therapeutics is that mammalian organisms have evolved a complex suite of responses to avoid infection by pathogens, as a result, RNA is effective in eliciting a variety of immune responses that ultimately aim to degrade a potentially infective organism as well as preventing entry into cells or even killing cells infected by this foreign genetic material.

Dose control is a potentially big challenge compared to biopharmaceuticals. This is largely linked to another shortcoming, which it is the delivery of mRNA, its stability in circulation, uptake by target cells (and stability inside cells) and translation potential.

This is perhaps why, most of the products registered and in development are vaccines. Immune activation by vaccines requires considerably lower amounts of product compared to other biopharmaceuticals, like monoclonal antibodies, which usually require large doses (up to 5-10g/Kg) to be effective.

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Corollary: Can it be made? Manufacturing at the crossroads of innovation

Some see all the issues mentioned above as an inevitable evil that one must face (fortune favours the brave), however, as I have been trying to present here, there is clearly a lot of mileage in investing time and resources in addressing at least some of these issues, both as a community (academic research as well as industry), but also as part of the development efforts of individual therapeutic entities, bringing together discovery (design) and development (including manufacturing) into a coordinated effort.

Designing the product for manufacturing and designing manufacturing processes for product success are paramount in ensuring the sustainability of drug development endeavours and the affordability and accessibility of medicines to patients, and it sits at the foundation of the QbD philosophy. In this line of though some aspects need also to be considered, for example supply chain security. Unfortunately, it still occurs that products can be discontinued because manufacturing becomes cost-prohibitive for patients and health care providers. So new / alternative manufacturing concepts and paradigms are needed to be considered, for example just-intime manufacturing, on-demand manufacturing, decentralised manufacturing, or manufacturing at point-of-care. Clearly most, if not all, of such concepts are ill at ease with the praxis currently favoured in the industry. However, it is not too far-fetched to envisage a future where medicine accessibility (and affordability) would require dramatic changes in how therapeutic treatments are produced and distributed.

If we look at the latter (manufacturing at pointof-care) proximity to patient is becoming a critical

61 CENTRAL RESEARCH

aspect for some therapies in development, particularly those involving living therapeutics, often with a limited shelf-life. Here supply chain logistics, full traceability and chain of custody become essential. Perhaps integration of new technologies, such as blockchain (secure encrypted ledger) could become a saviour to guarantee traceability, compliance whilst maintaining full confidentiality.

So, in conclusion, concerted efforts in the under- standing of active ingredients and their mode of action as well as in the design of the therapeutic product including APIs and delivery platforms (formulation, dosage form and device), will help developing medicines that are both effective and affordable to those that need them the most.

References & Footnotes

[1] Mahdavi B., Gottschalks, U., Trainor, N., & Smith T. (2015) The Medicine Maker 0915-502. Retrieved from: https://themedicinemaker.com/manufacture/the-hype-hopeand-reality-of-personalization

[2] Graham C, Jozwik A., Andrea Pepper A., & Benjamin R., (2018), Allogeneic CAR-T Cells: More than Ease of Access?, Cells 7, 155. Retrieved from: https://pubmed.ncbi. nlm.nih.gov/30275435, doi:10.3390/cells7100155.

[3] Raftery, M.J., Franzén, A.S. & Pecher, G. (2923) CAR NK Cells: The Future Is Now. Annual Review of Cancer Biology 7:229-246. https://doi.org/10.1146/annurevcancerbio-061521-082320

NOTE: The opinions expressed in this article belong exclusively to the author and do not necessarily represent his current employer’s official position in any of the topics covered.

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Project Nazare, the new augmented reality glasses Withings BeamO smart thermometer

Meta’s augmented reality glasses will hit the market in 2024 and will be renewed every two years. Project Nazare”, the name given to the device inside Mark Zuckerberg’s company, is developed by the creators of the Oculus (the first virtual reality glasses launched).

The gadget promises to become the Holy Grail of the modern world, redefining our relationship with technology and human interaction. These devices would become a fundamental tool to enter the “Metaverse”. The glasses will be able to introduce digital objects into the usual real-world experience. With the glasses you will be able to receive information directly to your eyes as if you were watching a “Black Mirror” episode.

Courtesy: Canal Viax

Nix, the biosensor that measures hydration levels

Nix is the new biometric device that allows personalized and accurate hydration analysis to determine how much water to drink.

It weighs around 14 grams and has a capacity of up to 36 hours of use per charge. The Nix patch was designed to measure specific biomarkers by capturing electrochemical data as sweat is secreted. This device provides athletes with personalized, scientifically validated hydration data delivered in real time.

Continuously measures sweat during workouts and sends personalized notifications to your phone or smartwatch in real time to indicate when, how much, and what they should drink to replenish lost nutrients and ensure optimal hydration.

Courtesy: Nixbiosensors.com

BeamO is a kind of small compact diagnostic center designed by Withings to measure body temperature on contact, perform electrocardiograms, and measure blood oxygenation level.

It can measure body temperature through automatic detection of the temporal artery, serves as a digital stethoscope to listen to the heart and lungs, and as a clinical-grade electrocardiogram to detect possible cardiovascular diseases at any time. It measures the level and saturation of oxygen in the blood, which can help evaluate part of your respiratory system, and BeamO detects atrial fibrillation and sends notifications if the heart rate is too low or too high.

Courtesy: Withings

63 GADGETS

Smart box bag that hits back

Boxing Buddy is an innovative sports assistance instrument consisting of two padded robotic arms that can be attached to a punching bag or any rugged vertical installation to provide a personalized and effective workout.

Through any smartphone, this product can be programmed in four difficulty levels and three different training modes, such as Random Sparring, where the arms are launched at random speeds and frequencies; Custom mode, where users have the freedom to program variables based on their specific needs and focus areas, and Coach mode, where a trainer controls the arms remotely and in real-time via the app. Boxing Buddy is currently priced at $299; its worldwide launch was in September 2023.

Courtesy: Boxing-buddy.com

Health & fitness tracker to a new level

The Tricorder.Zero health and fitness tracker is the new 7-sensor device for comprehensive body monitoring.

It features an ENT camera to visualize the ear, nose, and throat, a high magnification camera for the outside of the eye and skin, a thermometer for infrared temperature reading, a pulse oximeter to record heart rate and blood oxygenation percentage, a stethoscope to listen to heart, lung and abdominal sounds, an electrocardiogram sensor to visualize the pattern of electrical activity in the heart and a body fat sensor.

Courtesy: prelaunch.com

Physiotherapy massager for knees and joints

For $119.95, Carepeutic launched the new physiotherapy massager for knees and joints, which has four methods of therapy for rehabilitation in one device: thermal moxibustion, infrared heat therapy, magnetic therapy, and massage.

Its ergonomic design and adaptability, coupled with its superconducting acupressure massage, allow pain relief for knees, elbows, and shoulders.

This device promises to help improve muscle tissue stiffness, and reduce pain in the affected area and joint swelling. The default time for infrared heat therapy is 30 minutes.

Courtesy: Carepeutic

64 GADGETS
Clinical Research Insider Editorial

ENGINEER IN BIOLOGICAL SYSTEMS

Blanca M. Peredo VAzquez

Henrietta Lacks, The HeLa Cell Controversy and Good Clinical Practices

“The voluntary consent of the human subject is absolutely essential”

Excerpt from the Nuremberg Code of Medical Ethics

Henrietta Lacks (Hennie, for her family), was born on August 1, 1920, in Roanoke, Virginia, USA. Henrietta was part of a large family dedicated to tobacco growing. She lived a happy childhood, however, after the death of her mother and in the midst of the economic crisis of the time, her father made the decision to leave his children in the care of his close relatives.

Because of this, young Hennie went to live at her paternal grandparents’ home, which she always considered her family home. There Henrietta would meet her future husband David Lacks, who was her uncle’s son, and therefore Henrietta’s cousin. The Lacks family lived under the segregationist regime of the time, so their employment opportunities were limited. When she became pregnant in 1935 with David Lacks, Henrietta decided to leave the world of agriculture and seek new prospects in the city, where the family prospered thanks to the growing steel industry. Some time later, when Henrietta was only 31

years old, she went to Johns Hopkins Hospital for abnormal vaginal bleeding, where she was diagnosed with cervical cancer. From that moment on, she began a battle against cancer through treatments and techniques of the time, however, the tumor invaded her body. Hennie finally passed away on October 4, 1951 at 00:15 hours at Hopkins Hospital, and was buried in Lacks Town, near Clover.

HeLa cells

When Henrietta consulted Dr. Richard W. TeLinde (Gynecologist and Researcher at Hopkins Hospital), she underwent several studies, which determined that she had a cancerous tumor, so Dr. TeLinde decided to take biological samples to examine it, and these samples were sent to Dr. George Gey’s department.

Dr. Gey was obsessed with the creation of

66 Clinical Research Associate at Drox Health Science
PEOPLE IN SCIENCE

a cell culture of human origin that could be “immortalized”, as already existed in mice. As the director of the Cell Culture Department at Hopkins Hospital, he was able to design a study to create a cell line that would act on

cervical cancers and decrease their mortality rate. However, his experiments had not been successful and by the time Henrietta’s cells arrived at the laboratory, Dr. Gey cultured, analyzed and labeled them under the name HeLa.

At first, the cell’s growth rate was high, but instead of dying, as eventually expected, they doubled at a steady rate every 24 hours. So, by repeating the process, Dr. Gey had achieved an immortal cell line. The Tuskegee events saw the installation of the world’s largest HeLa cell factory, which was used exponentially to test the polio vaccine, saving millions of people.

Since then, HeLa cells have been used in medical treatments, traveled to space, were used

in atomic experiments, and were the first cells to be bought and sold by laboratories around the world. However, there was a problem. In the 1940s and 1950s, it was unclear whether it was necessary to ask for permission (informed consent) to use human tissues for research.

It wasn’t until 1973 that Henrietta’s family learned that their relative’s cells were still alive, so they consulted with lawyers to find out if they had rights to them; They have since been embroiled in legal battles.

Sources

Álvarez, A. (2013). Henrietta Lacks. The name behind the Hela cells, the first human immortal cell line. Revista Médica Clínica Las Condes, 24(4), 726-729. Retrieved from: https://doi.org/10.1016/s0716-8640(13)70214-1

BBC World News. (2023, 1 agosto). Henrietta Lacks, the woman of humble origins whose immortal cells saved millions of lives. BBC World News. Retrieved from: https://www.bbc.com/mundo/articles/cw48xelg555o Fuentes-Alburo, A. (2011, September 1). Remembering Henrietta Lacks (HELA). Gaceta Mexicana de Oncología. Retrieved from: https://www.elsevier.es/ es-revista-gaceta-mexicana-oncologia-305-articulo-recordando-henrietta-lackshela–X1665920111894243

67 PEOPLE IN SCIENCE

In 2021, the WHO held an event commemora-ting Henrietta and the many scientific advances thanks to HeLa cells, where the WHO Director-General said: “What happened to Henrietta was wrong, Henrietta Lacks was exploited. She is one of many women of color whose bodies have been misused by science”.

68 PEOPLE IN SCIENCE
The Mother of Modern Medicine by Kadir Nelson, oil on linen, 2017. Collection of the Smithsonian National Portrait Gallery and the National Museum of African American History and Culture, gift of Kadir Nelson and JKBN Group LLC.
CLIRTOON 69

Articles inside

Genetics, the science of the future

1min
page 11

Editorial no. 13

2min
page 5

The Expert's Opinion

3min
page 12

The Expert's Opinion

2min
page 13

Central Research

4min
pages 14-16

Ask The Mousecid

6min
pages 54-56

Central Research

8min
pages 24-28

Genetics, the science of the future

1min
pages 50-51

Central Research

6min
pages 46-49

Clinical Cosmos

4min
pages 30-32

Central Research

7min
pages 58-62

Latest News

5min
pages 6-8

Science Today

7min
pages 41-45

Clinical Cosmos

3min
pages 52-53

Business & Development

4min
pages 39-40

Science Today

8min
pages 34-38

Central Research

3min
pages 20-22

Insider Ranking

3min
pages 17-19

Latest News

5min
pages 6-8

People in Science

4min
pages 66-68
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