Development of a gene therapy strategy for the restoration of survival motor neuron protein expression: implications for spinal muscular atrophy therapy.

Spinal muscular atrophy (SMA) is a motor neuron degeneration disorder, and manifests itself in patients as muscle weakness and paralysis that ultimately leads to death. Currently, there is no effective treatment for this disease. As a first step in developing a treatment for SMA, we are examining whether delivery of the gene encoding survival motor neuron (SMN) protein to primary fibroblast cell lines derived from SMA patients can lead to restoration of nuclear-staining foci, called gems, which are absent in patients with severe SMA. Using adenovirus-mediated gene delivery, we show that SMN can be efficiently expressed in patient fibroblasts, and leads to restoration of nuclear gems, which are thought to be important for the functional rescue of the SMA phenotype. The number of gems per cell is equal to or greater than those found in fibroblasts of normal individuals. Furthermore, ectopic expression of SMN also caused relocalization of Gemin2, an SMN-interacting protein, to gems. Overall, this work is the first demonstration of the feasibility of virus-based delivery of the SMN-coding gene to restore the normal SMN expression pattern in SMA patient-derived cells, and holds promise for gene therapy of SMA, as a potential long-term therapy for this devastating childhood disease.