My long-term career plans are to investigate the etiology and treatment of neuromuscular diseases. One way to approach this problem is to study mutations that disrupt normal neural development. Proximal spinal muscular atrophy (SMA) is a prime example. After cystic fibrosis, SMA is the most common autosomal recessive childhood disease. The disease affects 1/10,000 live born children. It is characterized by degeneration of the a-motor neurons in the spinal cord, which causes proximal, symmetrical limb and trunk muscle weakness that progresses to paralysis and ultimately death. Currently, there is no available treatment for SMA patients. Clinical management consists of aggressive treatment of respiratory infections and prevention of trunk deformities through the use of braces or spinal fusion.
Mutations in survival motor neuron 1 (SMN1) gene are responsible for SMA. In humans, two virtually identical copies of SMN are present, SMN1 and SMN2. SMN1 produces only full-length transcripts (FL-SMN) and is therefore the SMA-determining gene, whereas the predominant transcript from SMN2 is an exon 7 alternatively spliced form (D7SMN). The SMN2 gene also produces a low level of FL-SMN transcript, which explains why SMA is not embryonic lethal in humans. Nevertheless, lower motor neurons eventually succumb to the reduced SMN dosage and degenerate. Why motor neurons are specifically affected is not clear but it has been proposed that this may be due to a distinct role for SMN in this cell type.
The mouse Smn gene is present as a single copy and does not undergo alternative splicing. Smn-/- mice are pre-implantation lethal and underscore the importance of the Smn protein for cellular survival. Efforts at generating mouse models of SMA have been encouraging but not entirely successful. The best model to date is the combination of an SMN2 BAC transgene on the Smn-/- background. In this model, there is either neonatal lethality at low SMN2 copy number or complete rescue at high SMN2 copy number. To further our understanding of SMN in terms of structure/function relationships and disease pathogenesis, it would be ideal if a panel of animals with intermediate/mild phenotypes of SMA existed.
My intent is to develop a strong translational research program for SMA. The research will be multi-faceted and use biochemistry, cell biology, molecular biology and animal modeling. We will use these approaches to decipher SMN function within nerve and muscle, the two tissues affected in SMA. We will also create a hypomorphic allelic series of Smn mutations in mice. This will provide a classical approach to study Smn function in vivo and determine the biochemical mechanism of motor neuron death in SMA. These animals will be an invaluable resource for testing potential treatment modalities in vivo. Finally, since a treatment for SMA may require both gene and pharmacological therapy, we are investigating the potential of delivering genes encoding either SMN or other neuroprotective agents to motor neurons in animal models of SMA. To this end, we have already demonstrated that cellular deficits in skin cells from severe SMA patients can be rescued through adenoviral delivery of SMN. We are now moving forward to test this strategy in animal models of SMA.