Genetic Medicines: Past and Future
Gene Therapy and Gene Editing
About the Authors: Mosha Deng is an Investment Fellow at Thornapple. He is currently pursuing a PhD in Bioengineering at the University of Pennsylvania focused on engineering next-generation chimeric antigen receptor (CAR) T cells for solid tumors. Prior to Penn, Mosha led Business Development & Licensing at Insmed Incorporated, a public-traded biotechnology company focused on developing novel treatments for rare and orphan diseases. Mosha also spent time in healthcare investment banking at UBS and Raymond James, advising clients in the biotechnology, medical device, and healthcare sectors on M&A and corporate finance matters. Mosha received his MSE in Bioengineering at the University of Pennsylvania. Prior to Penn, he earned a Bachelor of Business Administration from the Stephen M. Ross School of Business at the University of Michigan.
Max Beyman is an Investment Fellow at Thornapple. He is currently a first-year MBA candidate at the University of Chicago Booth School of Business. Prior to pursuing his MBA, he was a researcher at Regeneron Pharmaceuticals working on developing a gene therapy delivery platform, with a particular focus on optimizing AAV delivery and safety. Prior to Regeneron, Max worked at the NIH in the lab of Dr. Edward Lakatta and employed CRISPR-Cas9 techniques to study age-associated inflammation. Max received his Bachelor of Science in Molecular Genetics at the University of Rochester.
Introduction
Gene therapy and gene editing have revolutionized modern medicine and profoundly transformed the way diseases can be treated at the genetic level, much in the same way that monoclonal antibodies have reshaped precision medicine at the protein level. Despite a gold rush of activity from industry participants, the science of both fields is still in relatively early stages with different degrees of market fragmentation. Combing through the noise to identify promising assets or communicating a differentiated product will require a solid understanding of the science as well as market sentiment and dynamics. To assist with these efforts by our investment colleagues and operating partners, we have put together a whitepaper that summarizes the capabilities and limitations of various gene therapy and gene editing approaches, and identifies promising areas of investment. Some of our notable findings are included below as a preview — for more information, please contact team@thornapplecap.com.
While gene therapy and gene editing both leverage vastly improved understanding of the human genome and powerful biological innovations to dramatically alter disease outcomes, they are also distinct approaches with unique properties. Generally, gene therapy is the episomal or cytoplasmic delivery of larger DNA or RNA payloads to transiently correct genetic defects (often loss-of-function). Most gene editing approaches employ large protein complexes and often smaller DNA templates to directly modify the genome and correct mutations permanently. Yet, both can be delivered via viral or non-viral vectors and are thus affected by similar delivery limitations, among other factors.
Gene Therapy
In gene therapy, the primary challenge is delivering efficacious doses of the therapeutic payload to the appropriate cell type. The right cell varies by disease indication, but classically it is one where atypical expression of a protein or a cell can be used to produce therapeutic levels of a secreted protein. In essence, this is a delivery problem, and our paper will primarily focus on the two major classes of delivery modalities currently being developed, viral and non-viral, each with advantages and disadvantages. Payload optimization through synthetic biology also holds promise, but it may still need to be combined with delivery improvements to achieve therapeutic and safety benefits.
Besides the well-known technical challenges in delivery and immunogenicity, the field is also impacted by considerable market fragmentation compared to other biologic modalities. Landmark gene therapy approvals have prompted many non-traditional firms to jump into the foray, pushing many assets into the clinic across multiple disease indications. This offered investors a greater choice of investments but also increased the probability of a negative readthrough impacting the field. The risk is amplified as immunogenicity and delivery challenges become bigger roadblocks as therapies require more systemic administration and target less accessible tissue.
In contrast, there are effectively two mature players dominating the fields of mRNA medicine (Moderna and BioNTech) and RNA interference (RNAi) drugs (Alnylam and Ionis). While it may create innovation overreliance on a virtual duopoly, it also enables these firms to better control market sentiment and investor expectations. It would allow the technology to mature to a stage that is more amenable to participation from more diverse investors and firms.
Gene Editing
On the gene editing side, the field is still in its early stages despite an endorsement via a Nobel Prize in Chemistry in 2020. It will be some time before clear leaders are identified from a fast-growing field of ever more inventive methods, including CRISPR, base editing, and prime editing. As a result, preclinical and clinical failures are expected. Fortunately, the gene editing landscape is not as fragmented as gene therapy. Much of the innovation is concentrated in a few trailblazing firms, which allows the needed scientific trial-and-error process to occur in expert hands.
Specifically, many intrinsic and extrinsic factors influence therapeutic outcomes of gene editing and thus require optimization. Extensive research is being conducted to improve editing efficiency, minimize off-target risks, identify non-DSB (double-strand DNA breaks) approaches, enhance component delivery and other intrinsic properties. Other technical factors include whether the sgRNA binds to a coding strand already occupied by active transcription activity, the concentration of gene editing products delivered, and even as specific as the number of G and C bases contained in the target DNA sequence.
Yet, equally important is the understanding of target cell biology (immune, stromal, or stem cell-derived cells, etc.), donor source selection (autologous vs. allogeneic), disease pathology, and other gene editing extrinsic factors. Multidisciplinary teams that combine gene editing expertise with mechanistic disease understanding will be better equipped to push gene editing treatments into the clinic and to a successful regulatory outcome.
Summary
In our paper, we understand it will be challenging to comprehensively survey every unique or incremental approach and technical detail in two often separate fields of increasing depth. Thus, we elected to describe the most promising approaches in each domain, beginning with gene therapy with a particular focus on delivery system innovation (viral and non-viral). Then, we will walk through gene editing and touch on the latest techniques with the most potential (CRISPR, base editing, and prime editing). We are excited to share our takeaways with the community. Please write to us at team@thornapplecap.com if you would like to review our whitepaper and discuss with us afterwards.
