Gene therapies for neurogenetic disorders
Orrin Devinsky, Jeff Coller, Rebecca C. Ahrens‐Nicklas, X. Shawn Liu, Nadav Ahituv, Beverly L. Davidson, Kathie M. Bishop, Yael Weiss, Ana Mingorance
Abstract
Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.