Prepared by Kathryn J. Swoboda, MD
Director, Pediatric Motor Disorders Research Program, University of Utah School of Medicine

Several years ago, Chang and colleagues published the initial observation that sodium byturate appeared to improve survival and motor function in a mouse model of SMA. Spurred by these observations, Butchbach and colleagues in the Burghes laboratory at Ohio State University subsequently began to painstakingly study other butyrate derivatives. Some of these compounds, when administered early in the course of disease in the SMA animal model, significantly improved survival, but the timing of administration proved critically important. It was clear that the compounds varied in potency, and that any benefit diminished significantly if treatment intervention were delayed. However, one of these butyrate derivatives, sodium phenylbutyrate, had been in clinical use for decades in the treatment of newborn infants with urea cycle disorders. The hypothesis that this compound, given early in the course of the disease, might improve outcomes ultimately resulted in the launch of the STOP SMA study in 2006: a phase I/II open label Study of sodium phenylbutyrate in pre-symptomatic infants with Spinal Muscular Atrophy. These efforts have been generously supported by many: FightSMA, MDA, FSMA, and the Kylee Galbraith Memorial SMA Research Fund at the University of Utah, with medication graciously provided by Ucyclyd Pharma.

We completed enrollment for the STOP SMA trial in April 2010, and early results appear promising: of six infants expected to develop type I, survival and respiratory support needs are considerably improved compared to their affected siblings and symptomatic type I infants in the database, and one infant achieved independent sitting. In addition, two of six children expected to develop type II disease achieved independent walking. In addition to the improved motor outcomes, electrophysiologic data indicate that these children have less significant denervation than expected for age based on a natural history studies. However, the next few months will undoubtedly prove critical in moving this work forward to achieve the ultimate goal of this project: demonstrating the feasibility of rapid identification of newborns with SMA in order to permit early intervention for the many promising new therapies on the horizon.

Over the next year, we anticipate completion of the final dataset for the STOP SMA trial, data analysis and dissemination, development of a STOP SMA trial registry and database for prospectively identified SMA subjects, and planning for the next steps forward to identify infants via newborn screening, using a recently validated pilot newborn screening assay. For the STOP SMA protocol, we developed a proactive monitoring program with protocol-driven interventions for nutrition and respiratory care, modeled after the current cystic fibrosis clinic model. However, further pilot studies are necessary to determine how to best implement such a program in several states in anticipation of the launch of a nationwide prospective newborn follow-up program in infants diagnosed with SMA on newborn screening. Development of this database, and dissemination of best practices and proactive monitoring protocols to physicians and parents will improve the quality and length of life and the standard of care provided to children with SMA. We are extremely grateful for the additional funds provided via the Pepsi Challenge, Stop SMA and FightSMA at this crucial time to move this project forward as quickly and efficiently as possible.

Kathryn J. Swoboda, MD
Associate Professor, Neurology and Pediatrics
Diplomate, American Board of Medical Genetics
Director, Pediatric Motor Disorders Research Program
University of Utah School of Medicine

RICHMOND, VA — Richmond-based FightSMA, a nonprofit dedicated to developing a treatment for the deadly childhood crippler spinal muscular atrophy (SMA), is awarding a $250,000 research grant to Dr. Brian Kaspar, a principal investigator at Nationwide Children’s Hospital and associate professor of The Ohio State University.

The grant will support safety and toxicity studies for AAV(-9), a potential “delivery system” for gene therapy for the treatment of SMA. “Our SMA gene therapy program at Nationwide Children’s Hospital and The Ohio State University continues to show great promise for treating SMA patients,” said Dr. Kaspar. “With this award, we will be able to test our therapy for potential safety or toxicity issues and provide important information for the regulatory process as we advance our program to the clinic in a swift and safe manner. We are all very thankful for the support of FightSMA.”

The grant has been made possible by funding both from FightSMA (www.fightsma.org) and from its associated partner organization, the Gwendolyn Strong Foundation (www.gwendolynstrongfoundation.org). “We are tremendously excited about the potential for gene therapy in SMA and our continuing collaboration with the Gwendolyn Strong Foundation and the SMA Community,” said FightSMA President Martha Slay. “Gene therapy research is a marathon run, but the work of Dr. Kaspar will advance the field significantly for SMA.”

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. SMA is caused by the absence of a gene that is critical for muscle strength, the SMN (“survivor motor neuron”) gene. That gene is absent in approximately one in 30 individuals. If both a man and woman are lacking the necessary SMN gene, the chances are 25% that any of their children will manifest SMA.

An objective of gene therapy is the restoration of the missing gene through delivery systems called “vectors.” Adeno-associated virus (AAV) is considered to be an attractive candidate for the construction of vectors.

FightSMA was created in 1991 with the mission to “strategically accelerate the development of a treatment or a cure for spinal muscular atrophy.” Working with the guidance of an international Scientific Advisory Committee, FightSMA has awarded SMA research grants at more than 40 universities and research institutions in the United States, Canada, the United Kingdom, France, and Italy. FightSMA has chapters across the United States and in Canada.

For more information, contact: www.fightsma.org or 804.515.0080