Spinal muscular atrophy (SMA) is a neurodegenerative disease of the motor neuron that is caused by deletion or mutation of the survival motor neuron gene (SMN1). SMN1 encodes the survival motor neuron (SMN) protein that is important for the biogenesis of small nuclear ribonucleoprotein particles that are important for pre-mRNA splicing, but the splicing target involved in SMA pathogenesis remains unclear. Humans contain a second and partially functional SMN2, which contains one nucleotide difference in exon 7 compared to SMN1, leading to the skipping of exon 7 in most SMN2 transcripts and truncated SMN proteins. Limited amount of functional full-length SMN protein is expressed from SMN2 but it typically cannot compensate for the loss of SMN1. The loss of SMN protein causes debilitating muscle weakness, respiratory distress, and death in severe cases. SMA occurs at a frequency of one in 6,000 to one in 10,000 live births and it is the leading genetic cause of infant mortality in the United States. There is currently no treatment or prevention of the disease, although a number of approaches have been extensively researched as potential therapeutics. These approaches include gene therapy to deliver the SMN1 gene, and splicing modulation of SMN2 using anti-sense oligo or small molecules to increase the expression of full-length SMN proteins. In this project, we propose a new approach to compensate for the loss of SMN using recombinant SMN protein conjugated to a cell penetrating peptide (CPP). CPP are short (10-30 amino acids in length) and highly positively charged peptides that can bring its covalently conjugated molecular cargos (including DNA, RNA, peptide, and protein) into almost all cell types. In this proposal, we will evaluate the possibility of using CPP-SMN conjugate for SMA therapy.

R21NS085514

2014-07-01

2017-05-31