Systemic delivery of anti-sense oligonucleotide targeting a-synuclein for the treatment of multiple system atrophy.

Multiple System Atrophy (MSA) is a rare, sporadic, age-related synucleinopathy characterized by Parkinson-like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of a-synuclein (aSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. We recently utilized a peptide-mediated delivery method to systemically transport an anti-sense oligonucleotide (ASO) targeted to aSyn in a mouse model of MSA. We hypothesized that systemic delivery of aSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the aSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. Following monthly treatments of the aSyn ASO, we found increased myelination in the corpus callosum and the cerebellum. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall aSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide-mediated delivery of aSyn ASO was not taken up by oligodendrocytes. Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.