SMA Research Briefs: Gene Therapy, New SMA Mouse

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Spinal muscular atrophy (SMA) is a disease in which nerve cells that control muscles (motor neurons) in the spinal cord die, causing progressive weakness in the voluntary muscles. Recent research news includes advances in delivery methods for gene therapy treatment of SMA, and creation of a new mouse model that could help scientists better understand and develop treatments for the disease.   

'Intermediate' mouse model of SMA developed

A new SMA research mouse, called the SMN read-through mouse, embodies the features of milder types of SMA — a quality, its developers say, that may make it particularly well-suited for a role in SMA therapy development.

The new research mouse has a disease that mimics "chromosome 5" or "SMN-related" SMA, in which defects in the SMN1 gene lead to a deficiency of SMN protein. (SMN stands for survival motor neuron.)

Unlike two of the most commonly used SMA mouse models (called SMN2 and SMN delta7), in which the severity of symptoms includes drastically reduced life span ranging from five to 14 days, the new model has a life span that lasts anywhere from 18 to more than 100 days.

In addition, tests showed that SMN read-through mice achieve higher body weight and have greater strength and physical capabilities than mouse models of more severe forms of SMA — although they are still smaller in size, and have decreased strength and motor function when compared to unaffected mice.

Importantly, the researchers wrote, all of the components of the SMA disease process examined in the new mouse were significantly different than those in unaffected mice, demonstrating the potential utility for testing experimental SMA therapies in a longer-lived model.

Christian Lorson at the University of Missouri in Columbia, and colleagues from that institution and the University of Southern California in Los Angeles, reported findings online Feb. 13, 2013, in Human Molecular Genetics. Read the full results, for a fee: Development and Characterization of an SMN2-Based Intermediate Mouse Model of Spinal Muscular Atrophy.

MDA did not fund this study but currently supports Lorson's work on targeting skeletal muscle as a therapeutic strategy in SMA.

Genes delivered into muscles reach nerve cells in SMA mice

SMA mice that received muscle injections of the SMN1 gene (encased in an adeno-associated virus 9, or AAV9, delivery vehicle) had milder symptoms and lived significantly longer than untreated mice, a research team based at Institut de Myologie, Université Pierre et Marie Curie in Paris has reported. The findings, the team says, provide the first demonstration for the therapeutic efficacy of this delivery route in an SMA mouse model.

Mice that received the treatment lived an average of 163 days, while untreated mice lived an average of 12.

In addition, the treated mice demonstrated improvements in behavior. They lost less weight than untreated mice, although they remained smaller than unaffected control mice. None of the treated mice showed signs of motor dysfunction, and all were able to run and climb normally in their cages.

Investigators detected widespread SMN1 gene activity, including in the central nervous system, peripheral nervous system and in non-nervous system organs.

This "simple and practical method" for transferring genes to motor neurons may have potential for use in the treatment of motor neuron degeneration, the investigators wrote, noting that further studies are needed to compare the efficiency of intramuscular versus intravenous gene delivery.

The research team published its findings online Jan. 8, 2013, in Molecular Therapy. Read the full report for free: Intramuscular scAAV9-SMN Injection Mediates Widespread Gene Delivery to the Spinal Cord and Decreases Disease Severity in SMA Mice.

Gene therapy for SMA receives boost

A three-year, multimillion-dollar cooperative agreement between Nationwide Children's Hospital in Columbus, Ohio; the patient organization Families of SMA; and the National Institute of Neurological Disorders and Stroke (NINDS) aims to advance gene therapy for SMA.

As part of the agreement, NINDS (part of the National Institutes of Health) awarded $3,752,462 to Brian Kaspar, principal investigator in the Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, to support his work to develop a strategy for delivering gene therapy directly to the central nervous system as a treatment for SMA.

Kaspar's work involves using the emptied-out shell of a virus to deliver genetic material to its target. He previously has shown that adeno-associated virus 9 (AAV9) targeted motor neurons effectively.

Delivery of genes directly to the central nervous system could allow for smaller quantities of virus to be used, which increases the likelihood that the treatment could be used in people with SMA who are older and larger, says a press release about the agreement.

This cooperative award from NINDS will support preclinical work up to the filing of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration and initiation of human clinical trials.