CSF-Delivered Gene Therapy Shows Promise for Spinal Muscular Atrophy

ELK GROVE VILLAGE, Ill., Nov. 5, 2014 /PRNewswire-USNewswire/ -- A manuscript from the laboratory of Dr. Brian Kaspar of Nationwide Children's Hospital was recently published in the journal Molecular Therapy. The paper, "Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA—a dose response study in mice and nonhuman primates" is the first publication resulting from a groundbreaking collaboration between Cure SMA, the National Institute of Neurological Disorders and Stroke (NINDS), and Dr. Kaspar.

Beginning in 2010, Cure SMA made a series of grants to Dr. Kaspar to study gene therapy, also called gene transfer. Spinal muscular atrophy (SMA) is caused by a mutation in the survival motor neuron 1 gene (SMN1). Because of this mutation, the individual does not produce enough survival motor neuron (SMN) protein. Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells. Kaspar's laboratory discovered that Adeno-associated virus serotype 9 (AAV9) had the unique ability to cross the blood brain barrier and the Blood-Cerebrospinal Fluid Barrier (CSF).

Dr. Kaspar and his team have studied two approaches for SMA: an injection into a vein, a process known as systemic delivery which is currently in Phase I/2 clinical trials, and delivery directly into the cerebrospinal spinal fluid (CSF), a process known as CSF-delivered gene therapy.

Using the data generated with Cure SMA funding on the CSF-delivery of the drug, Dr. Kaspar and his team were able to secure a $4 million grant from NINDS in 2013, to develop this delivery approach for human clinical trials in SMA.

"Development of therapies requires collaboration of academics, advocacy, industry, and government—no single party has the resources to do this alone.  The collaboration between Dr. Brian Kaspar, Cure SMA, and the NIH is an exciting model in leveraging resources and expertise in the hope of accelerating therapy development for SMA," said Dr. John Porter, PhD, Program Director at the National Institute of Neurological Disorders and Stroke.

The results of this research collaboration are the subject of Dr. Kaspar's latest article. Using a one-time delivery of the AAV9 carrying the human SMN gene, the researchers found SMA animals, which typically die at 15 days of age, surpassed 280 days median survival, with many animals surviving past 400 days. This is a remarkable extension in survival with normal motor function.  Furthermore, the group tested this delivery approach in larger species and found significant targeting of motor neurons throughout the brain and spinal cord. 

Dr. Kaspar stated, "We are very pleased with the results of this study and are working diligently to advance a CSF route of delivery to human clinical trials for SMA. We are grateful for the support from Cure SMA and NINDS.  We stand at an exciting juncture in SMA research and clinical translation with strong will to see effective therapies for all those with SMA." 

"We are excited to see expansion of the gene therapeutic program and the potential to advance this route of delivery to patients with SMA.  The latest results supports further development of a CSF-delivered gene therapy treatment," said Jill Jarecki, PhD, Cure SMA's research director. 

Current Clinical Trials for SMA Gene Therapy

The technology for both systemic and CSF-delivered gene therapy has been licensed to AveXis, a clinical stage biotechnology company.  AveXis and Nationwide Children's Hospital are currently collaborating on a Phase I/2 clinical trial testing the systemic delivery method in infants with SMA. The trial (NCT02122952) opened for enrollment in Columbus, Ohio in April 2014 and is currently recruiting in the dose-escalation phase of the trial.

The CSF-delivered gene therapeutic is also advancing toward clinical trials. Cure SMA is currently developing third-year project plans with Dr. Kaspar to continue moving CSF-delivered gene therapy forward. In the next few months, we will announce the specifics of those plans.

"A critical long-term goal of the Cure SMA drug discovery approach is to help identify treatments for SMA patients with every type of the disease and at every stage of disease progress. CSF-delivered gene therapy is a major step toward that goal and this approach may reduce the amount of gene therapeutic required for larger and older patients," said Kenneth Hobby, president of Cure SMA.

Cure SMA would like to thank all those who have contributed funding for this particular program, including special gifts from The Michael and Chandra Rudd Foundation, The Miller McNeil Woodruff Foundation, and The Jacob Isaac Rappoport Foundation.

About Cure SMA
Cure SMA is dedicated to the treatment and cure of spinal muscular atrophy (SMA)—a disease that takes away a person's ability to walk, eat, or breathe. It is the number one genetic cause of death for infants.

Since 1984, we've directed and invested in comprehensive research that has shaped the scientific community's understanding of SMA. We are currently on the verge of breakthroughs in treatment that will strengthen our children's bodies, extend life, and lead to a cure.

We have deep expertise in every aspect of SMA—from the day-to-day realities to the nuances of care options—and until we have a cure, we'll do everything we can to support children and families affected by the disease.

Learn more about how you can help us reach a treatment and cure at www.cureSMA.org.

SOURCE Cure SMA

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