Human Molecular Genetics Advance Access originally published online on February 19, 2009
Human Molecular Genetics 2009 18(9):1600-1611; doi:10.1093/hmg/ddp076
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Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy
1 Department of Molecular Microbiology and Immunology and 2 Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
* To whom correspondence should be addressed at: Department of Veterinary Pathobiology, Bond Life Sciences Center, Room 471G, 1201 Rollins Road, University of Missouri, Columbia, MO 65211-7310, USA. Tel: +1 5738842219; Fax: +1 5738849395; Email: lorsonc{at}missouri.edu
Received January 12, 2009; Accepted February 12, 2009
Spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival motor neuron-1 (SMN1). A nearly identical copy gene, SMN2, is present in all SMA patients, which produces low levels of functional protein. Although the SMN2 coding sequence has the potential to produce normal, full-length SMN, 
90% of SMN2-derived transcripts are alternatively spliced and encode a truncated protein lacking the final coding exon (exon 7). SMN2, however, is an excellent therapeutic target. Previously, we developed bifunctional RNAs that bound SMN exon 7 and modulated SMN2 splicing. To optimize the efficiency of the bifunctional RNAs, a different antisense target was required. To this end, we genetically verified the identity of a putative intronic repressor and developed bifunctional RNAs that target this sequence. Consequently, there is a 2-fold mechanism of SMN induction: inhibition of the intronic repressor and recruitment of SR proteins via the SR recruitment sequence of the bifunctional RNA. The bifunctional RNAs effectively increased SMN in human primary SMA fibroblasts. Lead candidates were synthesized as 2'-O-methyl RNAs and were directly injected in the central nervous system of SMA mice. Single-RNA injections were able to illicit a robust induction of SMN protein in the brain and throughout the spinal column of neonatal SMA mice. In a severe model of SMA, mean life span was extended following the delivery of bifunctional RNAs. This technology has direct implications for the development of an SMA therapy, but also lends itself to a multitude of diseases caused by aberrant pre-mRNA splicing.
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