Proteolipid protein suppression for Pelizaeus Merzbacher Disease

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SUMMARY Pelizaeus-Merzbacher disease (PMD) is a severe X-linked pediatric neurodegenerative disorder impacting myelination in the central nervous system (CNS). PMD results from toxic gain of function mutations in the PLP1 gene which encodes the most prevalent myelin protein, proteolipid protein, of the CNS. PMD exhibits a spectrum of clinical phenotypes that reflect wide genotypic heterogeneity. The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to progressive neurological deterioration and death, often during childhood. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. In this proposal we will quantify the biological activity of antisense oligonucleotides (ASOs) to target and suppress aberrant proteolipid protein and measure the resulting therapeutic effect in PMD mouse (in vivo) and human (in vitro) models. During the R61 phase we will use proteolipid protein levels as a pharmacodynamic marker to inform dose ranges and regimens of ASOs. Additionally, we will measure variability of phenotypic endpoints in PMD models to ensure that all efficacy studies are appropriately powered. In the R33 phase, we will test the in vivo efficacy of ASOs to suppress proteolipid protein and enhance myelination and neurological function in a genomically accurate duplication mouse model of PMD. Additionally, we will test the efficacy of ASOs to suppress proteolipid protein and enhance human oligodendrocyte survival and function in oligocortical spheroids (organized 3D human CNS tissue-like structures) from a comprehensive panel of characterized induced pluripotent stem cell lines from PMD patients. Collectively, these studies will demonstrate whether PLP1-targeting ASOs have sufficient biological activity to warrant continued therapeutic development.