Central Research

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 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.

-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 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.

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.

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.

Antonio Carusillo, PhD

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.

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/