Drs. Mendell and Dunbar Reflect on NAM Election

Last month, ASGCT Past-President Cynthia E. Dunbar, M.D., and Members David R. Liu, Ph.D., and Jerry R. Mendell, M.D. were elected to the National Academy of Medicine (NAM). Drs. Dunbar, Liu, and Mendell joined 87 regular members and 10 international members elected this year who have demonstrated outstanding professional achievement and commitment to service, according to the announcement. 

Election to the Academy is considered one of the highest honors in the fields of health and medicine, so we asked the newly-elected NAM members a few questions. Read on to learn about accomplishments they are most proud of and what their election means for the field of gene and cell therapy.

Membership in NAM is based upon "distinguished professional achievement in a field related to medicine and health." Can you describe a contribution you have made to the field of gene and cell therapy that you feel the most proud of, and why?

JM: Over many decades my contributions to neuromuscular disease have improved the lives of infants and children. While it is humbling to be recognized by scientists in the NAM, the results of efforts that saved or improved the lives of affected infants and children are the most gratifying. My use of molecular tools dating back over 20 years to transfer genes to forms of muscular dystrophy and spinal muscular atrophy have paved a path for safety and efficacy for treatment of these devastating diseases. In addition, clinical trials using novel methods to achieve antisense oligonucleotide-induced exon skipping resulting in FDA approval for treatment of muscular dystrophy (EXONDYS 51®) has provided an alternative approach to promote gene expression and functional improvement in DMD subjects. Approval for exon skipping has further extended to include exon 53 (VYONDYS 53®) while exon 45 (Casimersen) has a pending new drug application approval. The field has now further exploded since GMP facilities are able to produce AAV in sufficient amounts to systemically transfer the SMN gene to infants with SMA type 1. Using the largest-ever doses of AAV to transfer SMN in a clinical trial, our success was a lifesaving treatment for infants expected to die by age two. Because of efficacy and safety, newborn screening for SMA has been approved in 31 states permitting treatment within the first few days of life for newborns carrying the mutant SMN gene. Treatment at this early point in time enables prevention of both symptoms and signs of disease. This product is now available on the market as Zolgensma and studies from the first trial in 2017 are beginning to allay fears that gene expression will shut down given that we see maintained or continued improvement years beyond viral delivery. Decades of frustrated effort devoted to changing the natural history of Duchenne muscular dystrophy (DMD) have now become a reality. DMD is the most common childhood neuromuscular disease and from what we learned by applying similar principles to DMD gene therapy trials, promising results are emerging for AAV gene delivery of a designer micro-dystrophin that will accommodate size and permit the transgene to fit the packaging capacity of the viral capsid. On the opposite end of the spectrum we have also been able to accommodate the larger size of the DYSF cDNA, >7kb, by dual vector packaging with a 1kb region of homology that permits homologous recombination upon gene delivery, achieving full DYSF gene expression in the clinical trial. The future looks bright for using these tools to benefit patients with severe neuromuscular diseases.

CD: My experience in the field was shaped by leading early clinical gene marking and gene therapy trials targeting hematopoietic stem and progenitor cells that were “unsuccessful” in terms of achieving high level stable gene transfer but instead pointed the way forward to the need for the development of more predictive preclinical models and a better understanding of target cells and the biology of gene transfer vectors. Since that time I have focused on the development of the predictive and clinically-relevant non-human primate model, using it to understand aspects of primate and thus human hematopoiesis relevant to gene therapies and the potential genotoxic risks of integrating viral vectors and gene editing. This stepwise work in a challenging model is perhaps hard to sum up in terms of a single advance , but I am thrilled my peers in the academy felt it worth of recognition, along with my contributions to  a new drug treatment for bone marrow failure that arose from my study of the role of thrombopoietin in supporting hematopoietic stem cells, initially as applied to ex vivo stem cell transduction.  I also believe my passionate commitment to career development, gender and ethnic diversity of the scientific and medical workforce, and focus on publication ethics as the editor of a major journal have also resulted in the peer recognition required for election to the Academy.

How will your membership in NAM advance or highlight gene therapy and your research?

JM: When I did my first gene therapy trial in 1999, the burden of many naysayers was pervasive, expressing the common notion that nothing could be achieved, and gene therapy would do nothing more than create clinical vegetables. Expressed fears included harboring an immune response to virus would be a burden waiting to insult the previously treated subject. We are all grateful to pioneers in our field who fought for moving the field to the next level, including the “Fathers of rAAV vectors” (Barrie Carter, Nick Muzyczka) and Jude Samulski for cloning wild-type AAV and to Terry Flotte for performing the first Phase I rAAV clinical trial for CF in 1996. As a long-time translational clinician scientist, I was lured into the gene therapy world based on the pioneering work of these scientists and believing that I could save the lives of affected patients.

Now with a powerful vector in hand, it seems more likely that we have the tools to repair the lives of infants and children with single-gene defects. NAM recognition helps spread the news of our current successes and invites young scientists to be recruited to the field and achieve heights never anticipated even a short time ago.

CD: I have already represented ASGCT on the National Academies Forum on Regenerative Medicine and saw firsthand the value of the NAM convening diverse constituencies to address challenging and fast-moving topics via public workshops, behind the scenes discussions resulting in consensus documents and simply having so many different points of view brought together. Now as an official Academy member, I can join other panels being convened on timely topics of relevance to gene and cell therapies and offer my voice as an investigator both with a deep appreciation and knowledge for the basic science advances as well as experiences caring for patients with life-threatening genetic and acquired blood disorders.

NAM is celebrating 50 years in 2020. Looking forward to the next 50 years, what do you think will be some of the biggest challenges in health and medicine, and what kind of role do you think scientists in gene and cell therapy have in alleviating them?

JM: The potential for gene therapy is far beyond anything we previously thought possible but it is hard to predict the challenges we face in the next 50 years. I think it is likely that the most promise is for single-gene disorders. For neuromuscular disease, we have made great strides in the most common conditions, but it will be important to expand the repertoire to conditions not currently targeted because they are very rare and associated with severe manifestations. As a neurologist I see the targets for gene therapy to be severe CNS diseases like GM1 gangliosidosis, GM 2 gangliosidosis (Tay-Sachs and Sandhoff disease), Menkes disease, and CDKL5 deficiency. I also see hope for acquired amyotrophic lateral sclerosis (ALS) without an associated gene defect, Lou Gehrig’s disease, a clear target given that ALS is one of the worst conditions afflicting patients in the prime of life resulting in total disability and death. As we move forward I also see CRISPR/Cas9 playing an important and major role for treatment of diseases with the greatest challenges.

CD: The last nine months have taught us that science and medicine must be able to pivot nimbly to address sudden emergencies such as SARS-CoV-2. The past 50 years have brought extraordinary advances in genomics, data science, structural biology, targeted drug discovery, immunology and virology, all resulting in the incredible speed of knowledge acquisition regarding SARS-CoV-2 and development of promising therapies and vaccines. The next 50 years will bring even larger challenges for humankind, particularly the impact of climate change and potential future pandemics. Techniques such as gene editing are already being explored to mitigate pandemics via introducing resistance into animal vectors or rapidly investigate and screen potential therapeutic approaches. But the biggest challenges are in communicating the value of science in the face of political currents painting knowledge and expertise as threatening or not believable. The NAM must focus on supporting the design and validation of approaches to convince people of the value and trustworthiness of the scientific method and the clinical development of new therapies, or the efforts of scientists and physicians will be in vain.

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