Neuromuscular Gene Therapy: Catching the Wave of Positive Early Studies Is Expected to Crest in Product Approvals (2019)

From any vantage point, there have been steady waves of discovery and encouraging early phase studies in the area of neuromuscular gene therapy. The marketing approval of Zolgensma (onasemnogene abeparvovec-xioi)—the first systemically delivered therapy for spinal muscular atrophy (SMA)—has certainly catalyzed the field of neuromuscular gene therapy and highlighted the challenges associated with early development in a field that has undergone explosive growth in the past 2 years since the first marketing approval of an adeno-associated viral (AAV) vector. For many genetically defined diseases affecting neuromuscular function, there have been limited therapeutic opportunities. Yet, a genetic medicine that addresses the root cause of the gene defect is expected to be a high-impact and disease-modifying therapy. The predominant approach in neuromuscular disease involves the use of non-integrating AAV vectors, which are particularly well suited for differentiated cells in the neuromuscular system. Since the musculature comprises 30%–40% of the body mass, the vascular route of delivery is the only practical approach to reach all of the musculature. Use of vectors that are capable of traversing the blood-brain barrier is an added bonus. Given the opportunity to reach body-wide musculature and the CNS using AAV vectors, it is not a surprise that neuromuscular gene therapy is at the forefront of the field. In order to ride the wave of success for neuromuscular gene therapy, it is important to emphasize the challenges that remain for clinical translation. For the majority of neuromuscular diseases there is a great deal known about disease pathophysiology and natural history. Therefore, designing an impactful gene therapy approach should be directed by these considerations. Terminally differentiated cells in the neuromuscular system, which are favorable targets for AAV-medicated gene therapy, are also subject to degeneration and may be permanently lost with disease progression. In the example of SMA, consideration of risk-benefit is strongly influenced by the rapid loss of motor neurons (by 6 months of age) in the most rapidly progressive form of the disease. The severe nature of SMA type 1 warrants an aggressive approach to systemic delivery of an AAV9 vector expressing SMN1. Improved outcomes are expected in the era of newborn screening for SMA, yet, since newborn screening is a federally recommended and state-sponsored enterprise, there is a very slow process to achieve US-wide implementation and limited availability outside of the US. For example, a treatment for Pompe disease was established in 2006 and the consideration of newborn screening was confirmed by expert review in 2007,1Kemper A.R. Hwu W.L. Lloyd-Puryear M. Kishnani P.S. Newborn screening for Pompe disease: synthesis of the evidence and development of screening recommendations.Pediatrics. 2007; 120: e1327-e1334Crossref PubMed Scopus (51) Google Scholar yet the official federal recommendation was not made until 2013,2Baker M. Griggs R. Byrne B. Connolly A.M. Finkel R. Grajkowska L. Haidet-Phillips A. Hagerty L. Ostrander R. Orlando L. et al.Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps.JAMA Neurol. 2019; (Published online May 20, 2019)https://doi.org/10.1001/jamaneurol.2019.1206Crossref PubMed Scopus (13) Google Scholar and US-wide implementation is still underway, over 10-years later, despite evidence of an important benefit.3Chien Y.H. Hwu W.L. Lee N.C. Pompe disease: early diagnosis and early treatment make a difference.Pediatr. Neonatol. 2013; 54: 219-227Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar There is a growing recognition that immune management will be required in neuromuscular gene therapy, especially in Duchenne muscular dystrophy (DMD), where total exposure to the AAV vector is a potent stimulus of innate and adaptive immune responses. Also, anti-transgene antibodies and cell-mediated immunity are not surprising in neuromuscular conditions where the therapeutic gene product is foreign in the setting of biallelic null mutations. There is non-clinical evidence of immune responses, which are especially problematic when observed in the heart, where high-level expression is favored by myocardial biodistrubition.4McTiernan C.F. Mathier M.A. Zhu X. Xiao X. Klein E. Swan C.H. Mehdi H. Gibson G. Trichel A.M. Glorioso J.C. et al.Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts.Gene Ther. 2007; 14: 1613-1622Crossref PubMed Scopus (30) Google Scholar This finding has been reported in one clinical study for young children with X-linked myotubular myopathy and is the basis for studies that prospectively block immune responses.5Corti M. Cleaver B. Clément N. Conlon T.J. Faris K.J. Wang G. Benson J. Tarantal A.F. Fuller D. Herzog R.W. Byrne B.J. Evaluation of Readministration of a Recombinant Adeno-Associated Virus Vector Expressing Acid Alpha-Glucosidase in Pompe Disease: Preclinical to Clinical Planning.Hum. Gene Ther. Clin. Dev. 2015; 26: 185-193Crossref PubMed Scopus (57) Google Scholar Similar strategies will be needed in the setting of pre-existing antibodies against the vector capsid, which currently exclude patients from participation in clinical studies. Early treatment will have the greatest opportunity to intervene before the loss of target cells, but earlier therapy may not be as durable since rapid somatic growth will lead to loss of the episomal AAV copies in muscle. Redosing strategies are currently being tested by our group, and the current data show that eliminating immune-mediated toxicity enhances overall safety. As the field of neuromuscular gene therapy has evolved to provide greater quantities of AAV for systemic administration, there is a growing need to establish rigorous comparability data to early proof-of-concept studies in rodents. In some cases, even non-human primate studies do not effectively model observations in adolescent or adult patients. Therefore, unanticipated findings may appear in the current era of neuromuscular gene therapy, and hopefully none of these lead to a stopping point of current studies. Additional consideration for AAV manufacturing relates to the consistency of AAV batch characteristics and reproducibility/comparability to early phase investigational product. Just to emphasize the drastic difference from commercial AAV production for ocular use to systemic use, the scale is 103 greater for infant patients and 1–2 × 104 times greater for adolescent or adult patients. Stakeholders need to intensify emphasis on this problem because the cost of commercial therapy will be a significant barrier for clinical use, even in the US, and cost prohibitive elsewhere in the world. In summary, a swell of excitement exists in the gene therapy community based on encouraging early findings that will significantly alter the disease course in neuromuscular disease. The availability of Zolgensma over the past 3 months will provide important lessons on how to best transfer knowledge from a limited number of study sites to many sites of service with variable levels of experience. In the era of commercial use for neuromuscular gene therapy, it will be important to have consistent and transparent reporting of outcomes and safety findings. Long-term follow up is a regulatory requirement; however, a comprehensive registry like the NeuroMuscular ObserVational Research (MOVR) initiative of the Muscular Dystrophy Association will be helpful across many care sites and disease types in order to establish the collective wisdom of using AAV-mediated gene therapy for neuromuscular disease.