Loss-of-function mutations in the survival motor neuron 1 (SMN1) gene cause the infant neurodegenerative disease spinal muscle atrophy (SMA). The majority of gene therapy-based therapeutic approaches to SMA rely on splice-switching oligonucleotides (SSOs) that modify splicing of a similar gene, SMN2, to generate functional SMN protein. However, these drugs require direct delivery into the CNS due to limited blood-brain barrier (BBB) penetration. In the Sep 12 PNAS, researchers led by Matthew Wood of the University of Oxford, U.K., report on a novel peptide-conjugated SSO, Pip6a-PMO, which effectively crosses the BBB. In newborn SMA model mice, two intravenous injections of Pip6a-PMO were sufficient to restore SMN protein expression, neuromuscular junction morphology, and motor coordination. The treated mice survived for 200 to 400+ days, whereas their untreated siblings died within two weeks. The team is now planning a clinical study in SMA patients.
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Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN, Meijboom KE, Zhou H, Muntoni F, Talbot K, Gait MJ, Wood MJ. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2016 Sep 12. Epub ahead of print.[Pubmed]