Multiple System Atrophy
Targeting misfolded toxic a-syn, a primary driver of Multiple System Atrophy (MSA)
MSA is a rare neurodegenerative disease with an estimated prevalence of 3.4-4.9 cases per 100,000. There is no effective treatment and the mean survival from the onset of symptoms is 6-10 years. The causative role of a-syn aggregates in MSA pathogenesis is supported by experimental evidence showing that a-syn aggregates from MSA brain homogenates propagate in a prion-like manner in vitro and in vivo, and cause MSA-like neurodegeneration in mice.
Using the ProMIS platform, several conformational epitopes were identified as likely to become exposed on misfolded, pathogenic forms of a-syn (toxic oligomers and soluble seeding fibrils). Monoclonal antibodies (mAbs) were raised against these epitopes and were tested for the desired binding profile and ability to protect neurons against toxic a-syn species in vitro. Multiple mAbs were screened and PMN442 emerged as the lead candidate for this program with the desired characteristics. PMN442 showed robust binding to a-syn oligomers and seeding fibrils, with negligible binding to a-syn monomers and physiologic tetramers which are required for normal neuronal function. PMN442 also reacted with native toxic a-syn present in brain homogenates from individuals with MSA and dementia with Lewy bodies (DLB). In activity assays, PMN442 protected rat dopaminergic neurons against killing by a-syn toxic oligomers.