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2019 / Vol. 9 / Issue-1

THE 10 MOST INNOVATIVE COMPANIES IN GENE THERAPY

Douglas Fambrough Co-founder, President & CEO

The Forefront of a Potential Revolution in Medicine


Editor-in-Chief Pooja M. Bansal Senior Editor Anish Miller Managing Editor Aishwarya Nawandhar Executive Editor Shambhavi Mhetre Visualiser David King Art & Design Head Amol Kamble Art & Design Assistant Poonam Mahajan Co-designer Paul Belin Art & Picture Editor Asha Bange Business Development Manager Peter Collins Marketing Manager Marry D’Souza Business Development Executive Mark Williams Sales Executives Sarah, Bill, John, Amy Technical Head Jacob Smile Assistant Technical Head Pratiksha Patil Technical Consultants David, Robert Digital Marketing Manager Alina Sege Assistant Digital Marketing Manager Prashant Chevale SME-SMO Executives Manoj, Gemson Research Analyst Eric Smith Circulation Manager Tanaji

September, 2019

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Editor’s Column

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rom the discovery of Penicillin to the use of numerous antibiotics to help treat patients today, we have come a long way. Back then, Penicillin was the miracle drug that treated infections considered as fatal and had no probable cure before this magic drug was invented. Recently, however, the stories of antibiotics resistance, emergence of new, dangerous diseases, have hit the headlines. Along with this, the story of the new-age miracle of medicine- Gene Therapy, is also reaching a number of people. So, what is gene therapy? Unlike the medicines that slow down the attack of diseases on our bodies, gene therapy is a method of treating or replacing the infected or non-functioning genes so as to end the disease at its root. Although it was first discovered in the 1980s, it is still in its infancy stage.

Is Gene Therapy the Next Big Miracle in Medicine?

Even then, there have been a number of clinical trials conducted and many success stories of not just treating, but curing some lifethreatening and chronic diseases, that were not treatable before this. A toddler in UK, born with an inherited immune system disorder, under went a pioneering treatment based on gene therapy. After this, he was watched closely for a few years and as if his parents’ prayer was answered, his immune system has been working normally. Apart from this, in some parts of the world, gene therapy has been leveraged to treat the inherited vision loss for the patients. Another interesting story reported recently was of the two brothers suffering from haemophilia, a genetic disease in which the body lacks the ability to clot the blood, even from minor wounds. Although, the treatment for it is available today, it reduces the quality of life, the patient’s freedom to do things and also reduces life-expectancy. Both the brothers enrolled for a clinical trial they heard of, which was related to a gene replacement technique with a possibility to aid cure haemophilia. The patient’s affected genes were removed and corrected and then transported back in the body using AAV virus. However, one of the brothers already had antibodies against AAV Virus in his body. The second brother is, today, living a healthy life, with his body producing the protein needed to clot the blood on its own. There are a large number of such cases around the world where gene therapy has come as an answer to several unmet medical conditions. Although it shows a lot of potential for revolutionizing the future of healthcare, there have been cases where the patients’ developed a sideeffect resulting in severe health conditions or even death. To exploit the benefits that gene therapy has to offer rightly, more research and better solutions need to be brought in. Also, the therapeutics based on this novel technique should be made affordable and accessible to all for it to bring a radical change in people’s lives!

Aishwarya Nawandhar


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Cover Story

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TS Article

24 Into the DNA

Gene Therapy: Changing the DNA of the Healthcare Space

Dicerna

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The Forefront of a Potential Revolution in Medicine

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Atvio Biotech Innovating and Developing Healthcare of Tomorrow

BioViva

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Reversing the Cycle of Aging with Gene Therapy

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Eukarÿs The Future of Synthetic Gene Therapy

Gracell Biotechnologies

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Conquering CAR-T Industry Hurdles with Futuristic Solutions

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VIROgene

Redefining the Future of Healthcare with Gene Therapy


Augmenting Healthcare with Novel Gene Therapy Solutions

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enes are what marks us different from every other person on this Earth. They contain DNA that defines the form and functions of any human body and any kind of defect in this lead to diseases. Unlike the medicines, gene therapy corrects these defects and stop the diseases once and for all. Additionally, medicines and treatments till date work on a trial and error method, prescribed according to the symptoms a patient’s body shows. However, every body type is dissimilar to one another and what may work for one person, doesn’t necessarily work perfectly for the other. With gene therapy, personalized medicines, made specifically for the person affected by a health condition, can be devised and this change from conventional healthcare to person-specific, will probably be the greatest revolution the industry would witness. In our issue of “The 10 Most Innovative Companies in Gene Therapy”, we are highlighting the stories of the leading companies that are catalyst to bring this revolutionary change. They are not only dedicated to aid in creating and offering therapeutics based on gene therapy, but also are working towards making it affordable for all. On the Cover, we have featured the inspiring story of DicernaTM Pharmaceuticals. It is a biopharmaceutical company using RNA interference, or RNAi, to create medicines that silence the genes that cause disease for patients with rare genetic diseases and common disorders. Apart from the cover story, the issue recognizes the contribution of the top companies that are transforming the healthcare industry with their next-gen solutions. These include ATVIO Biotech, a specialty cell & gene therapy (CTG) process development and innovation center; Gracell Biotechnologies, a clinical-stage biotech company with mission to solve CAR-T industry hurdles; Eukarys, a French biotechnology company that provides novel therapeutic solutions for the treatment of severe human disorders; VIROgene, a gene therapy startup that develops gene therapies on viral technologies that are not based on mammalian pathogens, to offer alternatives with a higher level of biosecurity; BioViva, a medical data analysis and research and development company that is leveraging gene therapy to accelerate the development of products that will effectively, and cost-efficiently treat biological aging; Oxford Biomedica; Puresyn; iCell Gene Therapeutics; and MeiraGTx. As you flip the pages, you will also find an interesting article on gene therapy from our in-house editor. Happy reading!


Douglas Fambrough Co-founder, President & CEO


The Forefront of a Potential Revolution in Medicine

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We aim to build a fully integrated company by developing innovative RNAi-based therapies for high unmet medical needs that reduce disease burden for all patients.

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C O V E R S T O R Y


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ounded in 2007 Dicerna Pharmaceuticals, Inc. is a publicly traded (Nasdaq: DRNA) biopharmaceutical company using RNA interference, or RNAi, to create medicines that silence the genes that cause disease for patients with rare genetic diseases and common disorders. It is a leader in RNAi, harnessing the potential of this powerful and complex process to investigate therapeutics that can enhance health, improve lives, and profoundly benefit patients with rare genetic diseases and common disorders. Dicerna aims to use its TM proprietary GalXC RNAi technology platform to develop therapies that are targeted, potent, and safe. The Brain Behind Dicerna

Douglas Fambrough, the Co-founder, President, and

partner with Oxford Bioscience Partners, a Boston-based venture capital firm. He co-created and served on the Board of Directors in Sirna Therapeutics in 2003. On behalf of Oxford, he invested in several ventures, including Solexa, developer of the dominant ultra-highthroughput DNA sequencing platform later acquired by which Illumina, and Xencor, a leader in engineering antibodies to improve their therapeutic properties. How it Started Following his scientific work, Douglas entered the VC industry with a goal of converting genomic technology and knowledge into useful medical advances. Pursuant to that goal, in 2003, he and two other investors created Sirna Therapeutics, a first-generation RNAi pioneer

We believe all patients deserve safe and effective medicines. Urgent patient needs drive our work to create new medicines with the potential to restore health.

Chief Executive Officer of Dicerna, is a genomic scientist and venture capitalist and has been instrumental in the evolution of the company from the very start. He obtained his PhD in genetics from University of California, Berkeley, and was a researcher at the Whitehead/MIT Center for Genome Research (now known as the Broad Institute). Throughout his career, he has worked in genetics to better understand the human genome and what causes disease. Douglas has led the company effectively, from the development of its unique GalXC platform, to Dicerna’s transformation into a successful, publicly traded company. Prior to joining Dicerna, Douglas specialized in financing innovative life science technology companies as a general

which was eventually acquired by Merck in 2006. Following the acquisition, Douglas decided to create Dicerna Pharmaceuticals to continue his quest to develop an RNAi therapy to address diseases with high unmet medical needs. This aim to reshape the healthcare industry by harnessing the power of genetic engineering ignited the flame of Dicerna. “Our vision is to build a fully integrated company that delivers innovative RNAi-based therapies to address high unmet medical needs. Ultimately, this will enable us to reduce disease burden for all patients while broadly capturing the value of our GalXC platform,” asserts Douglas.


Futuristic Solutions and Services Dicerna has invented the RNAi technology platform called GalXC, which is a proprietary technology platform that advances the development of next-generation RNAi based therapies designed to silence disease-driving genes in a broad range of serious diseases, including rare genetic diseases and common disorders. Dicerna is advancing a growing pipeline of product candidates to deliver transformative therapies to patients and currently has three GalXC programs in clinical trials and several more in early-stage development. Dicerna’s three clinical stage programs are DCR-PHXC, DCR-HBVS, and DCR-A1AT. DCR-PHXC is the only investigational RNAi drug in development for the

communities, policymakers, patients, and patient advocates. Dicerna has an open office plan in its current Cambridge headquarters, its new Lexington headquarters under construction, and its Boulder facility, that allows for the free exchange of ideas between people and teams. The Novel RNAi Technology Platform Dicerna’s proprietary GalXC platform allows development of RNAi therapies that are targeted, potent, and safe. The Dicerna GalXC molecules are structured to be processed by the enzyme Dicer, the initiation point for RNAi in the human cell cytoplasm. Unlike earlier generation RNAi molecules, which mimic the output product of Dicer processing, Dicerna’s DsiRNAs, including GalXC molecules, enter the RNAi pathway

We strive to create medicines using our GalXC RNAi technology that silence the genes that cause disease for patients with rare genetic diseases and common disorders.

The collaborative culture of Dicerna sets it apart from its contemporaries. It operates with a “no walls” philosophy. The company breaks down the barriers that slow the progress in rare diseases, like limited research, data, knowledge, and treatments. Additionally, it is committed to collaborating with the best and brightest, partnering with employees, industry, the medical and research

treatment of all three genetic types of primary hyperoxaluria (PH), a family of rare liver metabolic disorders. DCR-HBVS is being developed for the treatment of patients with chronic hepatitis B virus (HBV) infection and DCR-A1AT is being developed for patients with alpha-1 antitrypsin (A1AT) deficiencyassociated liver disease.

prior to Dicer processing. By using the Dicer enzyme as the entry point into the RNAi, Dicerna seeks to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion. Moreover, the GalXC RNAi platform does not involve lipid nanoparticles (LNPs) or other formulation components that facilitate drug delivery, simplifying the platform and eliminating any requirement for functional excipients. Instead, Dicerna’s GalXC molecules are stabilized by chemical modifications and utilize a four base sequence known as a tetraloop, where each base is conjugated to a simple sugar, N-acetylgalactosamine (GalNAc), that is specifically recognized by a receptor on the surface of hepatocyte liver cells. The tetraloop


Dedication, Innovation, Communication, Excellence, Respect, Needs based, Accountability- These are the values that reect the soul of Dicerna.

configuration, which is unique to Dicerna’s GalXC compounds, interfaces effectively with the RNAi machinery, allowing flexible and efficient conjugation to the targeting ligands, and stabilizing the RNAi duplex to enable effective delivery of Dicerna’s GalXC RNAiinducing molecules directly to the liver. Why RNAi? Since the inventers of RNAi, Dr. Craig Mello and Andrew Fire won the Nobel Prize in 2006, Dicerna’s scientists have been studying RNAi and working to optimize the technology in humans. As gene therapies and gene editing become better understood in the industry, the company is learning more and more about RNAi technology and how to develop innovative therapies. The scientists at Dicerna are experts in their respective fields, from biology to chemistry to experimental science, and more. Many of them present and participate in leading scientific and medical conferences and publish papers on RNAi and recent advancements in the space. Specifically using the RNAi process to treat disease, Dicerna leverages its several important advantages over other approaches to drug development: · RNAi does its work earlier in the disease-causing process. While some conventional therapies block the activity of proteins responsible for disease, RNAi therapies prevent these proteins from being created in the first place. · Unlike therapies that are too large to reach desired targets, RNAi can reach any target, including some of the most well-validated disease targets that are only expressed inside cells. · RNAi therapies can be considered a safer option than permanently editing the genes in your DNA. Directly editing the genes that cause disease can cause unintended effects to the genes needed to maintain good


health. RNAi addresses this risk because it is reversible, preventing protein building instead of editing the genes themselves. RNAi therapies have the potential for fewer side effects compared to small molecules and antibodies. · RNAi therapies also have the potential to reduce the treatment burden for patients. Their long duration of effect means they can be administered via an infrequent injection under the skin, also known as a subcutaneous injection. Pivotal Benchmarks in its Journey In its long and challenging journey of more than a decade, Dicerna has seen and leveraged various opportunities and overcome number of hurdles. On its way to success, there have been some major milestones: · November 2007 – Dicerna secured exclusive worldwide license for Dicer substrate short interfering RNA (DsiRNA), the inspiration for Dicerna's GalXC RNAi platform. · December 2011 – Dicerna received a U.S. patent for its Dicer Substrate™ technology, a precursor to its current GalXC platform. · June 2016 – Dicerna introduces GalXC, its proprietary, next-generation, RNAi technology platform. · November 2017 – Boehringer Ingelheim and Dicerna announce research collaboration and license agreement to develop novel GalXC RNAi therapies for chronic liver diseases, beginning with non-alcoholic steatohepatitis (NASH). · May 2018 – Dicerna initiates PHYOX™ Phase 1 clinical trial of DCR-PHXC in patients with primary hyperoxaluria type 1 (PH1) and type 2 (Ph2). · September 2018 – Dicerna presents successful proofof-concept data for DCR-PHXC for the treatment of primary hyperoxaluria. · October 2018 – Eli Lilly and Dicerna announce a global licensing and research collaboration focused on creating new medicines in cardiometabolic disease, neurodegeneration, and pain. Alexion Pharmaceuticals and Dicerna announce a collaboration to create RNAi therapies for complement-mediated diseases. · January 2019 – Dicerna initiates first dosing in Phase 1 clinical trial of DCR-HBVS for the treatment of hepatitis B virus infection. · July 2019 – Dicerna submits a clinical trial

authorization application to conduct a first-in-human Phase 1/2 study of DCR-A1AT for the treatment of alpha-1 antitrypsin (A1AT) deficiency-associated liver disease. · July 2019 – Dicerna doses the first patient in the PHYOX3 clinical trial. Valuable Collaborations Dicerna has active collaborations with three major biopharmaceutical companies: Eli Lilly and Company, Alexion Pharmaceuticals, and Boehringer Ingelheim International GmbH. All three companies are collaborating with Dicerna to apply the GalXC technology to therapeutic target genes to create new potential therapies for a variety of disease conditions. In total, more than $250 million in upfront payments, milestone payments, and equity investments have been made by these collaborators to Dicerna. Looking into the Future Dicerna is pursuing its vision with a clear and focused dual strategy. First, the company will pursue opportunities that address high unmet medical needs and that it foresees yielding both clinical and commercial success. The company’s clinical pipeline currently centers on two rare diseases: primary hyperoxaluria and alpha-1 antitrypsin deficiency-associated liver disease. The company plans to drive development and commercialization, either wholly or largely on its own, for both of these rare diseases. The other program is for a prevalent disease, chronic hepatitis B virus infection, for which it is seeking a development and commercialization partner once it has the Phase 1 proof-of-concept data. Secondly, Dicerna aims to realize the potential of its technology against all remaining targets through collaboration and discovery stage licensing agreements with therapeutic area leaders like Eli Lilly, Alexion, and Boehringer Ingelheim. Dicerna plans to own certain assets in the rare disease space that fit within the company’s strategy and will work with leading pharmaceutical partners to collaborate on assets for larger disease populations.


ATVIO BIOTECH Innovating and Developing Healthcare of Tomorrow

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dvanced cell and gene therapy is the future of medicine. It brings new hope and solutions for some severe diseases where conventional medicine fail to provide answers. Not just that, it has the potential to change the entire process of treatment in healthcare and for better. But the complexity, cost, and sensitivity involved in its production restrict its medical use. Overcoming these challenges will be a revolutionary breakthrough in the field of medicine. Turning this imagination into reality, Atvio Biotech Ltd. is redefining the future of healthcare. Atvio is a specialty cell & gene therapy (CTG) process development and innovation center. The company is a unique blend of scientists, biotech engineers, GMP experts, and engineering expertise, aiming to bridge the gap between science and technology. It believes that CTG is the future of medicine and without new and unique innovations, which will enable bringing the science to the patients, the industry will never deliver to its potential. Atvio is working towards making this a reality by combining its expertise with the therapy developers and innovating in the manufacturing space. The Multifaceted Persona Dr. Ohad Karnieli is the Founder and President of Atvio. He is a big believer of CTG and its potential for helping

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patients and has been in this industry for over two decades. In addition to being a scientist, Dr. Karnieli always had an attraction towards engineering and headed a medical device division in an Israeli company. This experience changed his perspective on what can be done with good engineers and tools. He headed technology and manufacturing at a prominent company where he got the chance to design a state-of-the-art facility and technology with highly talented team members. Like others, Dr. Karnieli identified the gap translating the science to the clinic. The difference was that he decided to take action and jump into the gap and build the bridge that would enable CTG companies to cross safely and bring their therapies to the patients. One of his biggest achievements is “infecting” a group of talented people with the vision of thinking differently and innovating to make therapies accessible to patients. The vision and spirit of helping bring lifesaving innovative therapies to patients, every day, drives him and the whole team of Atvio. The Journey of Atvio As the realization came to him, Dr. Karnieli set to influence the industry and help get treatment to the patients by extending his expertise not only to one company but to the industry, holistically. He then left the position of VP at his


previous company and started to dream of building a venture that would provide tools and development services to make therapies accessible to all. That is when Atvio was born! Believing that CTG is the future and providing a unique blend of scientific and development expertise with engineering skills is critical, he built a team of experts. However, getting the funds to start the company was not so easy. Dr. Karnieli overcame this challenge but was introduced to another one. Being based in Israel, Atvio realized that the industry for cell and gene therapy lied outside; in the US, the EU, and Asia. But Israel also brought with it an advantage of being the best place in the world to innovate with the best ecosystem and talent with a world winning record. Converting all its challenges to opportunities, Atvio has today emerged to be an excelling company in its field. The major breakthrough for Atvio was the presentation of ADVA CART device, which has been developed by Atvio for ADVA biotechnology. This device is a great example of the company’s unique offering. It will revolutionize the CART industry and will enable the therapy to patients all over the world at high availability and low price. Such a game-changing device could only be developed with the unique amalgamation of people and expertise Atvio offers. Hereafter, there was no looking back.

Dr. Ohad Karnieli Founder & President

Atvio allows cell therapy developers to focus on their scientific and medical challenges and utilize the expertise, tools, and knowledge it has, to get their product manufactured at quality, scale, and price. It is difficult for the companies to find all the needed experience and expertise in such a complicated evolving industry and this is where Atvio comes to their aid. It does everything, from gap analysis via simple process improvements to custom-made enabling solutions, such as the ADVA device or tailor-made bioreactors to fit the specific need. ADVA, a revolutionary product by Atvio, has brought to reality the vision of a device where you insert blood from one side and get CART from the other in a hospital. The company leverages its potential to overcome the bug challenges the industry faces. What makes the company stand out is its constant innovation, the unique blend of expertise, and the best and

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We are here to bridge science with the technologies, by turning great ideas to revolutionary cell therapy solutions

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Futuristic Products and Services

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most dedicated team one can find. Adding to that is the innovative and scientific ecosystem in Israel. Talking about his team, Dr. Karnieli asserts, “It’s all about the team! I have great team members who are dedicated, talented, and motivated to get the cell therapy to the patients. This blend of talent makes us unique and offers something different and better than anyone around.” A Long Way to Go Atvio’s latest focus is to build solutions such as the ADVA, which enable cost-effective, high-quality manufacturing at the point of care. The company always looks for and adopts new technologies and dares to try something new and better, every day. When asked about the future of Atvio, Dr. Karnieli says, “I see the company becoming stronger, validating our model and solutions, and starting to integrate unique tools and solutions with our partners on their therapies. I do believe our unique offering will be more prominent in the next few years, once people see the solutions we provide our partners.” Atvio believes that good science is the base of all therapies but without innovative manufacturing solutions and good development, patients will not be able to access them. This is exactly what the company is set to do.

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Elizabeth Parrish Founder & CEO

OUR VISION IS A WORLD IN WHICH INNOVATION AND SAFETY COME FIRST AND THROUGH FAST ACTION WE CREATE A WORLD WITH LESS SUFFERING

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Reversing the Cycle of Aging with Gene Therapy

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ioViva, a trail-blazing medical data analysis and research and development company, was started to change the face of healthcare treatments by bringing enhanced and definitive solutions for some of the most perilous diseases. The inspiration came from a lifechanging incident when the founder’s son was diagnosed with Type 1 Diabetes. On the path to find the most adequate treatment for him, she was confronted with the reality of children suffering from genetic diseases. She also discovered that, although laboratory animals have been successfully treated for many of these diseases, those therapies haven’t yet been made available to humans, because of the medical profession’s exaggerated risk aversion and the FDA’s precautionary attitude. This meant that despite the discovery of appropriate therapies, the kids die because these therapies have not yet been through a lengthy and extremely expensive chain of paperwork and clinical trials. Determined to change this condition, she established BioViva. Today, BioViva analyzes biomarkers from trials and studies involving patients referred to the clinics by its partner company, Integrated Health Systems. The company is focused on speeding up the number of medical innovations by cooperating with companies that offer consenting patients pioneering therapies that they cannot get in the United States. Using medical researchers to oversee the patients, it beats the gold standard of the US FDA and creates exponential technology for the future. BioViva is the first company in the world to look at the data of regenerative gene therapies in humans.

The Multi-faceted Kingpin Elizabeth Parrish, the Founder and CEO of BioViva, is a humanitarian, entrepreneur, innovator, author, podcaster, and a leading voice for genetic cures. As a strong proponent of progress and education for the advancement of regenerative medicine modalities, she serves as a motivational speaker to the public at large for the life sciences. She is actively involved in international educational media outreach. Dedicated to the cause of improving and safeguarding more and more lives, Elizabeth asserts, “We are focused on saving as many lives as possible by making tomorrow’s therapies available. This is about Life and Death. Risk aversion and the delaying the approval of therapies that have been successful in research simply kills.” Revolutionary Products BioViva provides gene testing kits that allow customers to learn information about their own genome from various perspectives, such as their biological age, risk for various diseases, etc. It is the only company in the world that has access to data from patients who are taking regenerative gene therapies. Additionally, the company is launching a multi-omics repository for clients to upload their data, regardless of what company they obtained it from, allowing the customer to have all their health data in one place. BioViva works in partnership with Integrated Health Systems to help people access advanced therapeutics. Concentrating on research and development, it is designing

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a new gene therapy delivery method to solve the very important problem of cell delivery of genes. The company also has an explicit focus on aging as a disease, because, according to BioViva, aging is a disease that underlies many others. “Time is your most valuable asset, we want you to have more of it. Creating a world with longer healthier lifespans gives us time to solve climate change and to come together as a species to solve social impact and reduce racism,” says Elizabeth.

master disease in this respect. By changing a set of genes such as the gene coding for the enzyme telomerase or the protein inhibitor follistatin, you can alter a person’s biological age, and thereby make him or her healthier, because youth is health, and old age is sickness. Aging is cellular degeneration over time, with gene therapy we can make the cell regenerate faster than it degenerates. I therefore regard gene therapy as the future, because it will address the scourge of aging with increased success, and we are working to offer first generation therapies to people who need them now.”

Shrewd Insight on Gene Therapy Into a Bright Future BioViva believes that gene therapy offers a permanent cure for a variety of diseases; it is the answer to monogenic diseases, such as progeria, and cystic fibrosis, as well to hemophilia b and sickle cell anemia. However according to the experts at BioViva, it also offers promise in the case of more complex diseases involving multiple genes. Addressing the same, Elizabeth says, “I regard aging as the

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BioViva has currently funded the Rutger’s University to work on developing a better vector for future gene therapy than the existing solution. It foresees that this project will be almost ready for future use in next five years. Additionally, the company hopes to have amassed the data that shows how different gene therapies, at least ten of them by 2024, have worked in humans, in the next five years.


Into the DNA

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THERAPY CHANGING THE DNA OF THE HEALTHCARE SPACE 24 | September 2019 |


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any questions arise on how amazing science is and how complicated nature can be! The human anatomy is created in a way that is very complex. There are around 7.7 billion people on the earth today and every single person is different from one another. Each individual has approximately 3 billion pairs of nucleotides and about 25,000 genes per cell. The base of any tissue is cells and the building blocks of all the cells are the nucleotides. Interestingly, the genes contain DNA that basically controls all the functions of a person. From the formation of various organs to the functioning and regulation of different parts of the body is possible due to the proper functioning of these small molecules. The genes are inherited by both the parents that make us stand out of the crowd. The uniqueness of an individual is reflected in all the aspects like physical traits including eye, skin, and hair color. Along with these traits, DNA is the main reason for a person’s behavior. There is an interesting question about how similar is human DNA? The answer to this is, 99.9% of the DNA composition of the human race is the same. However, what distinguishes

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us from each other is that 0.1%. Each person has a particular DNA sequence which is never similar to any other creature on this planet.

therapy, the effects of the process are not passed to the next generation.

There are many diseases and disorders caused mainly due to variations in the genes. Even a single mutation or change in the whole genome sequence can lead to some disorder. For a long time, researchers have been trying to find a technique that can help change these variations. An upcoming technique has given some hopes for solving this age-old problem. Gene therapy is an experimental technique that uses particular genes to treat or prevent the disease. Though gene therapy is at its infancy stage, it has been showing some promising results in various clinical trials. The treatment of inherited diseases or physical conditions can be a reality in the coming future with the help of gene therapy. This technique is used to add a new gene into the patient’s cell that is said to replace the missing or malfunctioning gene with a healthy copy of the gene. It may also be useful in inactivating a particular gene that has been causing a problem.

Germline Gene Therapy uses a section of DNA that is transferred to the cells which are involved in the production of eggs or sperm. The effects of this therapy are also seen in future generations.

There are mainly two types of gene therapy currently known that are being used in clinical trials all around the globe:

There are a few infectious diseases that are caused by the malfunctioning of a particular gene. Gene inhibition therapy is then used by introducing a new gene that blocks the faulty gene that leads to the proper functioning of the cell and ultimately treating the disease. A very good example is the treatment of oncogene that is the leading cancer-causing gene.

· Somatic Gene Therapy: In somatic gene therapy, usually, a piece or a section of DNA is transferred to the desired cell that is not involved in the production of eggs or sperm. The section of DNA is directly inserted in the body cells like the bone marrow. In this type of gene

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· Germline Gene Therapy

Gene therapy is practiced by three main techniques. Here are three techniques of gene therapy that are used: · Gene Augmentation Therapy: Various diseases that are caused by mutations are in the process of being treated by the gene augmentation therapy. In this, a gene is added to a cell that has a non-functioning gene. After the addition of this new gene, the cell functions normally, thereafter. A common example of gene augmentation therapy being used is for the treatment of cystic fibrosis. · Gene Inhibition Therapy:

· Killing Specific Gene Therapy: This technique is rather different. As

the name suggests, the technique kills a specific gene that is causing trouble. There are two ways in which a diseased cell can be destroyed. · In this type, a suicide gene is inserted into the cell that ultimately produces a toxic product leading to the death of the cell. · While in the second type, a marker gene is added so those marker proteins are exposed on the surface. The immune system then attacks the marker proteins that will destroy the cell later. It is said that diseases like cancer can be cured by this method. Ultimately, the cells die that are causing such diseases and disorders. This is a promising technique, though it has many challenges during the process. The main challenge is placing the gene in the right place. The crucial step after placing the gene correctly is switching it on. If the gene is placed in a wrong position in the cell, the gene will be ineffective and may cause severe health issues. While most of the time cells perform normally, it may happen that cell shuts down the genes. Sometimes, the new genes are treated as a potential harmful intruder. If the genes are misplaced, then they interfere with the functioning of the other genes. Although, there are many challenges, there is a wide range of potential applications of gene therapy in the treatment of various diseases. Diseases like cancer, cystic fibrosis, heart diseases, AIDS, hemophilia, diabetes, etc can be treated by this method. - Shambhavi Mhetre, Editor


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eadquartered at the Evry Genopole, Eukarÿs SAS (eukaryotic universal expression system) is a French biotechnology company. It was created to develop products and applications from the C3P3 expression system, including a radically novel therapeutic approach named synthetic gene therapy, and the development of C3P3 cellular systems to increase protein and virus bio-production yields. Eukarÿs developed the first ever non-viral eukaryotic expression system named C3P3 (chimeric cytoplasmic capping-prone phage polymerase) from the scratch. This artificial system generated by synthetic biology allows the autonomous production of messenger RNA (mRNA) in at high yields, and therefore the proteins of interest. The use the C3P3 system is decisive for the approach of synthetic gene therapy as it determines the effectiveness.

“ “ Eukarÿs' synthetic gene therapy is based on a proprietary synthetic DNA production system and the C3P3 system, which determines its safety, efficacy, and good tolerance, as well as its production at a reasonable cost. In addition, the structure of the synthetic DNA used in synthetic gene therapy allows its use not only for the rare genetic diseases, but also the most frequent multifactorial diseases for which

multiple genes or pathways should be targeted. Based on this generic synthetic gene therapy technology, Eukarÿs is developing a pipeline of treatments for severe diseases without therapeutic solutions. Its first treatments are targeted on liver diseases. The company's EUK-LPR, the first pro-regenerative treatment, which is the most advanced gene therapy treatment. It makes it possible to induce the regeneration of this organ before liver resection surgery. The first treatment trial of this on animals demonstrated its excellent efficacy and Eukarÿs has launched two new programs, one for liver diseases and the other for cancer therapy, which will be announced soon. The Leading Light of Eukarÿs Philippe JAÏS is the President and Scientific Director of Eukarÿs. He has a rich academic background with the degrees of MD, PhD, and MSc in physiology, molecular genetics, and biostatistics, respectively. He is a HepatoGastroenterologist and has specialized in molecular genetics of cancers as a PhD student and positional cloning as a post-doctoral fellow. He has served at various positions in a plethora of companies in the biotechnology industry, pharma companies in research, genetics, pharmacogenomics, translational medicine, genomic biomarkers, and early clinical development. Philippe has designed and realized the early clinical development and biomarker strategy of many small chemical molecules and therapeutic proteins. He also invented an approach for large-scale identification of human monogenic pathologies treatable by synthetic chemical ligands of nuclear receptors. In 2009, Philippe invented the C3P3 technology that he developed until its proof of concept, before cofounding Eukarÿs. He has published more than fifty articles, books and abstracts, and is the inventor of several patents including all those of the company.

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The Ingenious Solution Eukarÿs has developed a unique non-viral, non-infectious, and non-integrative named synthetic gene therapy approach. This synthetic gene therapy exploits the C3P3 system and determines the effectiveness. In addition, the artificial DNA used for the synthetic gene therapy by Eukarÿs explains its safety, good tolerance, as well as its production at a reasonable cost. Moreover, the modular structure of these treatments makes them usable with minimal adaptation for the majority of human diseases, including monogenic and multifactorial disorders, which is virtually impossible for most existing gene therapy methods. Although usable for the treatment of many organ diseases, the initial goal of the company is the creation of a pipeline of synthetic gene therapy treatments for severe liver diseases and diseases related to deficiencies in secreted proteins, with significant unmet medical needs. They have now extended this pipeline to oncology for the treatment of very frequent cancer. In a business prospective, Eukarÿs develops its own pipeline, but is open to partnerships with Pharma and Biotech companies. The most interesting factor of the company which differentiates it from the rest is that all its technologies were developed from scratch and are under constant evolution. Why Synthetic Gene Therapy? “Today, gene therapy can only be used for some ultra-rare and ultra-severe diseases in some ultra-rich countries. Our ambition is to make synthetic gene therapy accessible to a large number of patients for a large number of diseases today without a therapeutic solution,” says Philippe. Eukarÿs' synthetic gene therapy approach excels all others. Gene therapy needs to be safe: The risk of integration of virus leading to cancer limits the use of viral gene therapy to ultra-severe disorders for which the risk is acceptable. Eukarÿs synthetic gene therapy is devoid of this risk. Gene therapy needs to be well-tolerated: Viral gene therapies, as well as the synthetic RNA are usually poorly tolerated, which is a significant drawback, especially for chronic disorders. Eukarÿs gene therapy uses a specific design of the synthetic DNA, which explains the good tolerance of synthetic gene therapy and allows its long-term uses.

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Gene therapy has to be efficient: The classical non-viral gene therapy and the synthetic RNA are notably inefficient because the amount of target mRNA produced or uptaken by the cells with these technologies is drastically low. The synthetic DNA exploits the performances of the C3P3 expression system, which is a proficient system to produce high amounts of target mRNA in the cells. Gene therapy should economically accessible: Today, the cost of production of a single dose for patient of recombinant virus is ranging from €200,000-€600,000! In addition, due to the immunogenicity and/or the episomal nature of the viral gene therapy, re administration of viral gene therapy is probably needed every few years, which increases its costs further. In contrast, the synthetic DNA used for Eukarÿs' synthetic gene therapy can be produced at reasonable cost. Gene therapy should be used for a broad number of diseases and not some ultra-rare monogenic disorders: This is not only due to cost of viral gene therapy, but also due to technical limitations, since only one small genes can be used for viral vector constructions. In contrast, the synthetic DNA used by Eukarÿs can assemble several genes with no length limitations. Therefore, Eukarÿs' synthetic gene therapy can be used not only for the rare genetic diseases, but also the most frequent multifactorial diseases. Awards and Accolades Eukarÿs has won several awards through the years. This includes, French Competition “Concours de Création d'Entreprises de Technologie Innovantes” in 2009 and a second time in 2011 in the Creation category, which is the highest possible reward, Techninov award, and Ubistart award. Additionally, the company was also labeled as Young Innovative Company by the French Ministry of Research and Innovative Biocluster Enterprise by Polinvest's from the Ile-de-France Medicen Competitiveness Cluster. What's Ahead? Eukarÿs aims to demonstrate the efficacy of the synthetic gene therapy in phase I/IIa clinical study, in 2023. It anticipates that this will introduce the company on the public market. It, then, plans to extend its therapeutic approach to many other therapeutic fields. In 2022-2023, Eukarÿs also anticipates of creating a subsidiary or a branch of Eukarÿs dedicated to protein and virus bio-production using the C3P3 technology, possibly in the USA.


GRACELL

Biotechnologies CONQUERING CAR-T INDUSTRY HURDLES WITH FUTURISTIC SOLUTIONS

T

he healthcare industry needs to bring in more effective solutions at affordable prices for all its unsolved questions. Cancer treatment is one of the major focus areas in this. There are various techniques and treatment solutions being devised in this area and a lot more are still under the research stage. CAR-T is one such technique that has shown a lot of potential to combat cancer. Although, it has already been developed, owing to CAR-T’s high costs and complex development procedure, it has not reached all of the population. To rectify this and to find better solutions against cancer, Gracell Biotechnologies is relentlessly working and innovating its way to a highly advanced and better future. Gracell Biotechnologies is a clinical-stage biotech company with mission to solve CAR-T industry hurdles. The aim to solve the problems like high cost of goods, lengthy and ineffective manufacturing process, lack of off-the-shelf products, and high relapse rate even with the achievement of complete remission for hematological malignancies. Being committed to research and development, it is bringing novel cell therapies with highly cost-effectiveness from the lab to the bedside. Gracell aims to bring best-in-class and affordable cellular medicines to the cancer patients. Founded in 2017, Gracell has today built a state-of-theart 44,000 sq. ft. R&D center in Shanghai and 63,000 sq. ft. GMP facility in Suzhou with an additional plant reserved for future commercial needs and advanced

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multiple IND filings. Currently, the company has over 90 talented FTEs. A Numero Uno Wei (William) CAO is the Founder, Chairman, and CEO of Gracell. He is a seasoned front runner with over three decades of experience in biotech and R&D. Before formulating his ideas into Gracell today, he co-founded and was the former CEO of Nasdaq listed CBMG; served at the former senior scientific management positions at Chiron and Affymetrix. William also has over 50 issued patents and applications for advanced cell therapies. He has built Gracell from scratch and has shaped its success with his rich experience. Talking about the company, he says, “Gracell’s mission is to make drugs accessible to ordinary patients. Many of the patients we see now in our clinical studies are not welloff. This mission is what keeps us going through the ups and downs of biotech entrepreneurship.” The Problem Chimeric antigen receptor or CAR-T cells are genetically engineered T cells, redirected to bind and kill tumor cells. These T cells, taken from patients’ own (autologous) or healthy donor’s (allogenic) blood, with activation, modification, and expansion, are administered to the patients. Preparation of conventional CAR-T cells can take weeks of processing, with high cost of goods.


We want to make drugs accessible to all by resolving the major challenges of cellular gene

therapy industry Wei (William) CAO

Founder, Chairman, and CEO

For patients at late-stage, with very limited life expectancy, long manufacturing time may compromise the medical benefits. Gracell’s Solutions Gracell is developing next generation CAR-T for advanced hematological malignancies, including leukemia, lymphoma and myeloma. It has multiple platform technologies and product candidates currently under clinical evaluations. FasT CAR FasT CAR is proprietary and patented technology of Gracell. Unlike conventional CAR, FasT CAR production only takes overnight for cell culturing. This results in affordable and highly cost-effective solution for patients. GC007F (anti-CD19), Gracell’s one of the lead program, is redirected to target B cell acute lymphoblastic leukemia (B-ALL). This product of the company has multiple advantages, including younger phenotype, higher proliferation capabilities, less

exhaustion, more potent eliminating leukemia malignancies, capability to infiltrate into bone marrow, etc. With all these features, clinical study has further demonstrated its remarkable outcome. Proving the effectiveness of GC007F, on 25th May 2019, 13/13 patients under test achieved complete remission under at least 28 days follow-up, with only mild side effects. Concluding, GC007F has the potential to be best-in-class anti-CD19 CAR-T profile. UCAR3 Lymphocytes from certain portion of patients cannot be adequately expanded to generate sufficient quality CAR-T cells. With this hurdle in the mind, Gracell is developing its own solution that would provide much better cost economics, mass production per lot, and followed by one-shot release, not specific to each individual patient. UCAR3 will be purely for off-the-shelf use. UCAR3 technology of Gracell is based on lymphocytes obtained from healthy donors and modified with gene

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editing to avoid GvHD as well as rejection. Genetic modification also helps protect from host versus graft (HvG) reaction and to enhance UCAR3 T cell persistence and proliferation. The company’s lead program is focused on treatment for T cell malignancies, and it is to enroll patients soon. In addition to FasT CAR and UCAR3, Gracell has been developing Enhanced CAR-T and Dual CAR-T platform technologies. These are currently under clinical evaluations. What’s Different? Among number of other competitors, Gracell is making its own mark and making its presence evident. Gracell has set up strong alliance with top tier hospitals; a network of 18 3A hospitals nationwide and a total 50,000-beds capacity. Additionally, with advances in cellular immunotherapy therapeutics, Gracell has obtained a strong support from the government, with subsidy, tax incentives, and perspective commercial land issuance. The most important aspect that sets Gracell apart is its capability to expedite product development. This significantly relies on its well-built and highly efficient team, in regard to process and assay development, regulatory compliance, facility engineering, and clinical functions. Moreover, the company does not just rely on in-house R&D activities, it also believes that external partnership can enhance and extend its capabilities and strengths. Gracell has a strong interest in the areas of immuno-oncology and cellular and gene-edited therapeutics that drives clinical unmet needs and is open to co-development and licensing opportunity. Further Roadmap Speaking of the CAR-T industry’s problems, William asserts, “The CAR-T industry is still in its infancy and I realized there are still many imperfections with the technology.” He continues, “As a drug developer, we shall be compensating as well as be responsible for those patients who cannot obtain clinical benefits from current standard of care.” Gracell is planning to submit its first filing by the 3rd quarter of 2019 and its new GMP facility will be open to operation by the first quarter of 2020. Additionally, it plans to start IPO within next twothree years. Gracell envisions to become the global leader in cellular cancer immunotherapy. 34 | September 2019 |


VIROgene Redefining the Future of Healthcare with Gene Therapy prominent healthcare organization walking arm in arm with the latest developments in technology is VIROgene, a gene therapy startup based in Buenos Aires. The company was established in 2017 by a group of biotechnology and medicine professionals having enriching experience in genetic engineering, molecular engineering, synthetic biology and medicine.

A

Laboratory of Universidad Nacional de Quilmes in Buenos Aires. After finishing his thesis, Martin asked his thesis partner and his Director, Dr. Mariano Belaich, to build a gene therapy startup company. He then started to participate in contests and events to look for funding. The central focus was on veterinary medicine in the first place to reach the market in less time, and then to focus on human medicine.

With its multidisciplinary team of renowned academics, developers, and clinicians, VIROgene is uniquely positioned to translate the technology into veterinary and human therapeutics. It designs innovative therapies using genetic engineering and synthetic biology applied to a broad range of viruses, and optimizes the development of therapies to solve health issues.

State-of-the-art Services Gene and immune therapies are nowadays the most promising treatments for a great number of genetic diseases including cancer, diabetes, and hemophilia. VIROgene’s prototype, V5, is a gene and immune therapy for mammalian tumor treatment. This unique therapy combines the high transduction efficiency and high gene expression of viruses, with the design of novel logic gates that trigger cellular and immunological responses. Although, many veterinary and human therapies exist to fight oncologic processes (chemotherapy, immunotherapy, radiotherapy and extractive surgery), some of them might compromise the patient’s physiological homeostasis, in different grades, making the entire organism susceptible to opportunist pathologies or even worse, creating new ones.

About the Leading Light Martin Williams, a biotechnology professional, is the CEO and Founder of VIROgene. With his unwavering passion and effort, he raised and built this revolutionary leading Gene Therapy Startup. His core purpose behind the inception of the company was to explore and build technological paths with a differential imprint to those already existing in the field of frontier molecular medicine. He believes, “Genes can be very effective therapeutic drugs when other strategies do not offer adequate solutions. Also, it is an incredibly exciting time to be a part of the Gene Therapy Revolution”. An Inspiring Journey It all started when Martin was pursuing his biotechnology studies and decided to take his degree thesis in gene therapy. Having a deep passion for genetic engineering and synthetic biology as well as in human and animal diseases, he always wished to start a company based on his knowledge in these fields. During the time, he looked for a lab to make his thesis and found the Genetic Engineering

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VIROgene is more focused on developing diabetes and hemophilia gene therapies as well, and vaccines using Virus Like Particles (VLPs) to trigger immune response against a broad range of pathogens. To bring in more innovation to its work, VIROgene develops gene therapies on viral technologies that are not based on mammalian pathogens, to offer alternatives with a higher level of biosecurity. Setting Itself Apart VIROgene is pioneering the development of life-changing treatments for severe diseases with engineered viruses that harbor therapeutic genes to cure diseases at the molecular


and cellular level. This novel platform is built on the discovery that viruses can instruct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructions that can have therapeutic activity inside and outside of cells giving the human body the capabilities to develop targeted lifesaving therapeutics. This approach also allows the intracellular production of therapeutic RNA. The startup has multidisciplinary group of professionals that are continuously developing new technologies to be at top of the ladder. Implementing synthetic biology, they are capable of creating complex gene circuits that allow them to adjust cellular activity in a right way. On the top of all these characteristics, VIROgene uses non-infective virus, making its therapies highly safe. Besides, getting into the molecular level, the company’s engineered genetic circuits are based on the design of logic gates that assure the appropriate response to a certain cellular activity. All these features make its therapeutics very attractive to markets.

CEO & Founder

Our vision is to build a global leading and integrated company that exploits its technology to deliver transformative gene therapy products to patients (domestic animals and humans) with severe medical conditions

Martin Williams

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Moving ahead with Evolving Science VIROgene is moving very close to the revolution in which great therapeutics will help thousands of lives. “Science is really tricky, and there are many uncontrolled factors in this environment that must be adjusted. Not everything is going to go perfectly and smoothly, but there is an endless effort underway that inspires everyone involved. Part of the diseases we work on, are ones that profoundly affect lives, and that´s why we are committed with that, and this has a significant impact in the development of human and animals’ therapeutics,” says Martin. The company believes that everything it develops starts with the science and leads to the medicine and that there are many “firsts” along this journey that get repeated. It believes that ‘We have to be disruptors for change in a system that does not know how to deal with disruption.’ In 2017, the Argentinian Science and Technology ministry recognized VIROgene as ‘One of the Most Innovative StartUps in Argentina’ for developing a novel cancer gene therapy prototype. Also, in 2018, they were selected as ‘One of the Most Disruptive StartUps in Argentina’.

Future Endeavour Today, there are a few gene therapies that are in clinical trial phase III for genetic diseases such as cancer, diabetes, hemophilia, Duchenne´s Muscular Dystrophy, and from those therapies, few are being developed for animals (Canine, Feline, Equine, and other companion animals). Hence, VIROgene ensures to stay at pace with the latest developments through everyday brainstorming and research, and using technology that allows to develop novel and biosafe therapeutics. VIROgene strives to generate solutions using disruptive technology in the human and veterinary medicine and to offer novel and effective alternatives to conventional treatments, enabling precise and corrective therapeutics. The company also plans to increment its developments for a diverse range of genetic and non-genetic diseases and also to develop novel-engineered viral systems that lend greater effectiveness to those available. “We see VIROgene as a leading global company, developing novel and disruptive treatments for severe human and animal conditions,” says Martin.

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The 10 Most Innovative Companies in Gene Therapy  

Insights Care has curated a list of “The 10 Most Innovative Companies in Gene Therapy”, we are highlighting the stories of the leading compa...

The 10 Most Innovative Companies in Gene Therapy  

Insights Care has curated a list of “The 10 Most Innovative Companies in Gene Therapy”, we are highlighting the stories of the leading compa...

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