The Promise and Challenges of Gene Editing in Drug Development

1. How can conventional ADME test systems be adapted to support gene editing technologies?

Dr. Chris Bohl: Conventional ADME test systems can support gene editing technologies in a couple of ways. The first is most advantageous for groups that are specifically targeting the liver for their gene editing treatment. Using cryoplateable primary hepatocytes, scientists can assess the efficiency of targeted changes made to the delivery system, editing machinery, and/or hepatocyte genotype/phenotype changes due to the editing. Utilizing various experimental designs, each of the editing steps can be assessed independently.

The second is advantageous to all gene editing programs. Long-term, micro patterned co-cultures using primary hepatocytes (HEPATOPAC®) can give insights into potential off-target toxicity caused by gene editing platform(s). Many gene editing delivery approaches utilize or lead to systemic dispersion of the therapy throughout the body. Even if the liver is not specifically targeted, it is very likely that the therapy will encounter the liver and other highly vascularized tissues. This exposure has the potential to inadvertently edit hepatocytes are only in the liver. This may lead to unforeseen off-target hepatic toxicity. Utilizing primary hepatocyte cultures that stay viable and active for many weeks, scientists can utilize the extended time in culture to examine the effect of chronic exposure of the gene editing platform and phenotype changes associated with off-target editing. This data may provide insight into predicting hepatic risks involved with their gene editing programs. These long-term cultures can also be built with additional cell types, such as Kupffer cells (HEPATOMUNE®), which might be useful as they add the resident hepatic macrophages back into the test system. This could help them understand potential risks of negative effects on co-administered treatments due to immune cell activation, cytokine release, and decreases in hepatic drug metabolizing enzymes.

In addition to hepatocytes, conventional tissue subcellular fractions and plasma/serum are used in cell and gene therapy programs to assess the stability of the platform while in circulation, much like their use in traditional small molecule assays. These in vitro test systems will help scientists test and optimize their platforms as well as reduce the amount of in vivo studies.

2. What are the main regulatory challenges associated with gene editing in clinical trials, and how can they be addressed?

Dr. Daniel Kavanagh: Major regulatory issues for this class of products include the potential for off-target changes in the chromosome, potential for inadvertent germ-line modification affecting future generations, and the need for long-term follow-up to monitor for safety and efficacy.

An additional concern is biosafety. For viruses and nanoparticles capable of making permanent alterations in a human chromosome, biosafety guidance and oversight for shipping, storage, administration, and disposal are critical. Addressing these challenges requires continuous cooperation and communication among statutory regulators and funding agencies. This includes maintaining appropriate risk-based oversight by Institutional Biosafety Committees (IBCs).

3. How have recent advancements in gene editing technologies, such as CRISPR, influenced drug development?

Dr. Chris Bohl: I think it has generated a lot of excitement and energy in the drug development field. It has opened a new avenue to explore in the effort to treat disease indications that were thought to be untreatable using other strategies/modalities. It has led biotech and pharma companies to open new programs and lines of research, brought new technologies and new scientists with different types of training into the drug development field, and created new bioprocesses and challenges for engineers to solve. But most importantly, these new technologies have given hope to families that there could be new therapies, or even functional cures, on the horizon that could increase the quality of life for their loved ones.

Dr. Daniel Kavanagh: Most public attention may be focused on medicines for which the mechanism of action is based on genetic modification of human chromosomes. Gene editing has also been tremendously useful at the preclinical discovery stage, for creation of cells lines for high-throughput small molecule screening. Gene editing can also be used to create better and more relevant animal model systems for preclinical testing.

4. How do you foresee gene editing impacting the pharmaceutical market in the next decade?

Dr. Chris Bohl: This new technology has the potential to positively impact a lot of families, but I expect the impact of these new therapies will not be fully realized market-wide for some time. I believe that adoption beyond those that are afflicted by rare, monogenetic diseases where there are no current or foreseeable treatments will take significant effort. I think it will take considerable time and coordinated effort to convince people that these treatments exhibit positive long-term safety profiles and have acceptable risks. The difficulty in attesting to safety is that we simply don’t have enough data points from the clinic nor full understanding of which in vitro safety tests/assays will be needed to predict safety in the clinic. Development of predictive in vitro test systems will be a crucial step towards developing safe and efficacious gene editing therapies.

Dr. Daniel Kavanagh: Some gene editing approaches will result in curing otherwise incurable conditions, potentially via a one-and-done treatment. This creates challenges for manufacturers and payers working to fairly address the needs of commercialization, reimbursement and accessibility. We are already seeing proposals with a lot of innovative suggestions, and the final implementation of specific reimbursement models is likely to have a large effect on this sector in the next decade.

5. How important is collaboration between research institutions, pharmaceutical companies, and regulatory bodies in advancing gene editing technologies?

Dr. Chris Bohl: I think collaborations between research groups and regulatory bodies are essential for the development, advancement, and wide acceptance of these new types of therapies. Even though these technologies have been in use in research labs for more than a decade, their use as disease therapies is so novel that they generate so many new questions. Open and transparent discussions between experts in the field can only be advantageous for moving more gene editing therapies into the clinic with helping as many people as possible. Open and frank discussions between groups, combined with data sharing, would go a long way toward calming fears and reducing hesitancy regarding wider use and accelerated development.

Dr. Daniel Kavanagh: These collaborations are certainly extremely important. Originally CRISPR DNA sequences were discovered through curiosity-driven basic science, and this type of basic research must be preserved. At the same time, scientists at research institutions can be better educated about the path from discovery to commercialization for potentially useful new technologies. Development of cell and gene therapy products at institutions can benefit from a clear understanding of commercial and regulatory requirements for manufacturing and distribution at scale. Collaborative guidance from companies and regulators is a critical aspect of this process.

6. Are there notable case studies or real-world applications of gene editing that highlight its potential or challenges?

Dr. Chris Bohl: I feel that the general population’s mood towards acceptance and trust in therapies that utilize gene modifying components will be a major challenge in achieving widespread acceptance and use. In addition, costs and ensuring availability will be major challenges that governments and private health insurance companies will have to work through to ensure that these therapies reach those who need them.

Dr. Daniel Kavanagh: We are already hearing personal stories from patients experiencing tremendous life-changing benefits from an FDA-approved product. There is obviously a potential to see this success repeated many times in a broad array of therapeutic areas. A real-world challenge affecting any investigational or commercialized treatment that changes DNA—especially genome editing—is long-term follow-up and safety monitoring.

7. What future trends or technologies in gene editing are you most excited about?

Dr. Chris Bohl: I think the natural evolution of these therapies is to expand to complex diseases that have polygenic/multi-factorial etiologies. As our understanding of genetic variability and its contribution to disease expands, new targets or groups of targets will emerge. This will hopefully lead to treatments that can help increase the quality of life for broader populations and more diverse disease indications.

Dr. Daniel Kavanagh: One thing that I find especially exciting is the potential for incorporation of gene editing into every aspect of medicine, in combination with small molecules, biologics, and devices. Years ago, computer science was a discrete endeavor with specialized applications, but today silicon chips are routinely incorporated into industrial and consumer products in every sector. DNA has always been the core determining element in human health and disease. The ability to precisely alter DNA has almost unlimited potential to enhance the effectiveness of other classes of medical products.

8. What key message would you like to convey about the future of gene editing in drug development?

Dr. Chris Bohl: Even with all the challenges facing the field, I believe that science will develop the tools needed to accelerate the development of gene editing therapies that will have the potential to bring life changing treatments to patients and their families. It opens the possibility of one-time treatments, functional cures, and therapy for diseases where no specific treatments are currently available. While setbacks are to be expected, I am confident that the field will be successful in developing the tools needed to bring more of these therapies to the market.

Dr. Daniel Kavanagh: I think the key message is always to look for appropriate technology. Gene editing is not a single tool. It is a set of related approaches that will evolve and expand over time. When one product succeeds, that does not mean that that exact same technology can be replicated for other applications. If one product fails, that does not imply a broad challenge to the validity of gene editing as an approach. I recommend hopeful enthusiasm without irrational exuberance.

Thank you, panelists, for your valuable insights on “Gene Editing in Drug Development.” Your expertise and perspectives have greatly enhanced our understanding of this complex field. We appreciate your time and the engaging information you provided.

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