Spinal muscular atrophy (SMA) is the most common form of motor neuron disease. It is the most common fatal genetic disease of infants, and the second most common (after cystic fibrosis) autosomal recessive genetic disorder. Nationwide Children’s Hospital's SMA Clinical Research Unit is the only center in the world that has carried out clinical trials in all three major forms of the disease. Several trials are ongoing and additional trials are in the planning stages. To that end, Nationwide Children’s Hospital participates in the Families of SMA-sponsored “Project Cure SMA” an international consortium of medical centers performing clinical trials in SMA.
Developing a Transgene to Help Determine the Best Timing for SMN Replacement in SMA
Proximal spinal muscular atrophy (SMA) is caused by low levels of the SMN protein. Mouse models of SMA can be rescued by increased SMN expression, but the timing of SMN replacement for complete rescue is unknown. This study features a temporally inducible SMN transgene that can be used to identify the therapeutic window for SMN replacement.
Access an abstract of this study: Generation of a tamoxifen inducible SMN mouse for temporal SMN replacement. Genesis. 2011 Apr 29. doi: 10.1002/dvg.20764. [Epub ahead of print]
Early Heart Failure Seen in Mouse Model of SMA
Mice models of severe SMA show signs of compromised cardiac functioning. Gene delivery was able to significantly decrease the severity of the heart defect in these mice. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings.
Access an abstract of this study: Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet. 2010 Oct 15;19(20):3895-905.
Gene Therapy Strategy Reverses Effects of SMA in Mice
Reversing a protein deficiency through gene therapy can correct motor function, restore nerve signals and improve survival in mice that serve as a model for spinal muscular atrophy. The researchers used an altered virus to deliver a portion of DNA that makes the SMN protein into the veins of newborn mice ranging in age from 1 to 10 days old. The SMN-laced viral vector injected into the youngest mice reached almost half of their motor neurons, resulting in improved muscle coordination, properly working electrical signals to the muscles and longer survival than in untreated mice.
Access an abstract of this study: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4.
A New Mouse Model for Adult Onset Form of SMA
Investigators present the Smn C>T mouse, which represents a new model for an adult onset form of SMA (type III/IV) also know as the Kugelberg-Welander disease.
Access an abstract of this study: A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype. Hum Mol Genet. 2010 Nov 1;19(21):4239-52.
Novel Gene Delivery Development for Spinal Muscular Atrophy, National Institutes of Health, National Institute of Neurological Disorders and Stroke (Brian K. Kaspar)
Optimizing Titer and Window of Opportunity for Targeting Motor Neurons via an AAV9 Vector, Families of SMA (Brian K. Kaspar)
Pre-Clinical Safety Studies of AAV9-SMN to Support a Pre-IND FDA, Fight SMA (Brian Kaspar)
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