Abstract
Spinal Muscular Atrophy is an autosomal recessive neuromuscular disorder that is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present called SMN2. SMN2 is retained in all SMA patients and encodes an identical protein compared to SMN1, however, SMN1 and SMN2 differ by a silent C to T transition at the 5' end of exon 7. This single nucleotide difference results in the production of an alternatively spliced isoform called SMN-delta7 that encodes an unstable and non-functional protein. Even though the majority of SMN2-derived transcripts lack exon 7, the presence of SMN2 represents a unique therapeutic target because SMN2 has the capacity to encode a fully functional protein. Here we describe an in vivo delivery system for short bi-functional RNAs that modulate SMN2 splicing. Bi-functional RNAs derive their name due to the presence of two functional domains: an RNA sequence that is complimentary to a specific cellular RNA (e.g. SMN exon 7); and an untethered RNA segment that serves as a sequence-specific binding platform for cellular splicing factors, such as SR proteins. Plasmid-based and recombinant adeno-associated virus vectors were developed that expressed bi-functional RNAs that stimulated SMN2 exon 7 inclusion and full-length SMN protein in patient fibroblasts. These experiments provide a mechanism to modulate splicing from a variety of genetic contexts and directly demonstrate a novel therapeutic approach for SMA.
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