Out-licensing

Development of a Knockout-Transgenic Mouse Model of Spinal Muscular Atrophy

Introduction/Background

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord leading to muscular paralysis with muscular atrophy. Clinical diagnosis of the disease is based on progressive symmetric weakness and atrophy of the proximal muscles. Affected individuals are usually classified into three groups according to the age of onset and progression of the disease. Type I SMA, also known as Werdnig-Hoffnan disease, is most severe, and affected children usually show SMA symptoms before 6 months of age and rarely live beyond the age of 2 years. Type II and Type III SMA are less severe, and the onset of symptoms varies between 6 months and 17 years of age. SMA is one of the most common foetal autosomal recessive diseases, with a carrier rate of 1-3% in the general population and an incidence of 1 in 10,000 newborns. Homozygous mutation of the telomeric SMN (SMNT) gene in humans is associated with proximal SMA.

Aims/Hypothesis

To further understand the functional role of the SMN gene in SMA, we produced mouse lines carrying a knockout mutation of the mouse Smn gene and transgenic mouse lines that expressed the human centromeric SMN (SMNC gene).

Research

Mice with the homozygous Smn knockout mutation died during the peri-implantation stage. Transgenic mice harbouring the human SMNC with the Smn gene knockout showed pathological changes in spinal cord and skeletal muscle similar to SMA patients. The knockout-transgenic mice clearly demonstrated that the SMNT gene is responsible for SMA and should be useful in elucidating the molecular mechanisms of the SMN gene and in the design of therapeutic protocols for SMA patients.

Conclusion

A genetically engineered mouse model has been developed that genotypically and phenotypically mimics human patients with spinal muscular atrophy.

Relevance/Opportunity

Please enquire quoting reference no. 13A-880510 if you are interested in forming licensing or codevelopment partnerships.

Preclinical

US6245963;