Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy
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Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Team Representative:
Jerry Mendell, MD
Principal Investigator, Nationwide Children's Hospital
Phone: (614) 722-5615

Media Contact:
Gina Bericchia
Phone: (614) 355-0487

Summary of findings in layman's terms:

Dr. Mendell’s clinical trial was published in the New England Journal of Medicine (NEJM) in early November 2017 and was the subject of simultaneous commentaries in NEJM and Science. He tested, for the first time in history, intravenous gene replacement therapy for a fatal disease in infants, spinal muscular atrophy. The work was conducted by Dr. Mendell and his multidisciplinary team at Nationwide Children’s Hospital in collaboration with AveXis, Inc. and The Ohio State University College of Medicine.

SMA1 is a devastating, progressive neuromuscular disease in infants caused by a mutation in a single gene, SMN. Affected children fail to meet motor milestones and typically die or require permanent mechanical ventilation by 2 years of age. In the Nationwide Children’s Hospital trial, a one-time intravenous injection of modified adeno-associated virus serotype 9 (AAV9) delivered the SMN gene to 15 affected infants. Three received a low dose, while 12 infants received a high dose. Those in the high dose group demonstrated improvement in motor function and a decreased need for supportive care compared to the natural history of the disease.

At the end of the study period, all 15 infants had to have a favorable safety outcome. Of the 12 patients treated with the highest dose, 92 percent achieved head control, 75 percent rolled over and 92 percent sat with assistance. Seventy-five percent of the infants are now sitting for 30 seconds or longer. Two can crawl, pull to a stand and walk independently.

According to the natural history of the disease, patients with SMA1 require nutritional and respiratory support by 12 months, and are not able to swallow or speak effectively. Of the patients who received the high dose in study, 11 patients are able to speak, and 11 patients are fed orally as of the data cut-off (August 7, 2017). 

Specific biological innovation of study: 

This first-of-a-kind clinical trial builds on nearly three decades of research led by collaborative teams at Nationwide Children’s and Ohio State’s University College of Medicine. Multiple iterative scientific advances enabled the work.

A key early development was establishment at the Ohio State University of a SMA mouse model that recapitulates the human disease. At the same time, foundational studies of adeno-associated virus (AAV) biology and unique AAV vector production methods for its use as gene therapeutics were conducted at Nationwide Children’s Hospital. A pivotal discovery for Dr. Mendell was made in the laboratory of the senior author of the NEJM study, Brian Kaspar PhD, at Nationwide Children’s. He found a specific serotype of AAV, AAV9, crosses the blood brain barrier when injected intravenously in experimental mice. This seminal work was published in Nature Biotechnology and garnered a beautiful cover image. The prospect for successful delivery of therapeutic genes into to spinal motor neurons by intravenous injection was clear. Important human diseases such as SMA and amyotrophic lateral sclerosis (ALS) are spinal motor neurons and the investigative team logically turned to the animal model of SMA.

Ohio State and Nationwide Children’s Hospital scientists collaborated to show that scAAV9-SMN, when delivered to newborn SMA mice, completely prevented the fatal neuromuscular disorder. Conceptually related studies were successful in a large animal model. Approximately the same time, a dedicated AAV Good Manufacturing Practices facility was constructed on the campus of Nationwide Children’s Hospital and a regulatory science core resource was put into place to produce high titer virus and navigate the path to FDA approval of a clinical trial. Following Dr. Mendell’s successful phase I trial described in the NEJM publication, additional studies to enable FDA approval of the first gene therapeutic for a fatal disease of infants are now underway. 

Potential impact on patient care and/or how the findings contributed to an improved understanding:

The SMA gene replacement therapy developed by the Mendell and Kaspar teams at Nationwide Children’s Hospital and collaborators at Ohio State University has the realistic potential to cure a devastating neurological disorder of newborn infants. Because of the inherent nature of gene therapy, a single dose, phase 1 trial has the potential to save lives. To date, this appears to be the case in 15 infants with the single gene disorder SMA. A powerfully succinct summary of the significance the NEJM report was made by Dr. Jim Wilson, a gene therapy pioneer at the University of Pennsylvania in a Science online commentary published contemporaneously with the NEJM manuscript. Dr. Wilson says “This was not a modest improvement. This is a transformational change. That’s what we had always hoped gene therapy would be.” (Gene therapy’s new hope: A neuron-targeting virus is saving infant lives. Science Nov. 1, 2017).

This study is a beautiful example of multidisciplinary team science at partnering academic institutions advancing a life-saving therapeutic from the laboratory, to preclinical studies, deftly though complex regulatory pathway, to the clinic and – with final FDA approval – hopefully into the marketplace.

Journal citation: 

Jerry R. Mendell, M.D., Samiah Al-Zaidy, M.D., Richard Shell, M.D., W. Dave Arnold, M.D., Louise R. Rodino-Klapac, Ph.D., Thomas W. Prior, Ph.D., Linda Lowes, P.T., Ph.D., Lindsay Alfano, D.P.T., Katherine Berry, P.T., Kathleen Church, M.S.W., John T. Kissel, M.D., Sukumar Nagendran, M.D., James L’Italien, Ph.D., Douglas M. Sproule,M.D., Courtney Wells, B.S., Jessica A. Cardenas,Ph.D., Marjet D. Heitzer, Ph.D., Allan Kaspar, Ph.D., Sarah Corcoran, B.S., Lyndsey Braun, B.S., Shibi Likhite, Ph.D., Carlos Miranda, Ph.D., Kathrin Meyer, Ph.D., K.D. Foust, Ph.D., Arthur H.M. Burghes, Ph.D., and Brian K. Kaspar, Ph.D. 

N EnglJ Med 2017; 377:1713-1722November 2,2017DOI: 10.1056/NEJMoa1706198