Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice

Conversion of glial cells into functional neurons represents a potential therapeutic approach for replenishing neuronal loss associated with neurodegenerative diseases and brain injury. Previous attempts in this area using expression of transcription factors were hindered by the low conversion efficiency and failure of generating desired neuronal types in vivo. Here, we report that downregulation of a single RNA-binding protein, polypyrimidine tract-binding protein 1 (Ptbp1), using in vivo viral delivery of a recently developed RNA-targeting CRISPR system CasRx, resulted in the conversion of Müller glia into retinal ganglion cells (RGCs) with a high efficiency, leading to the alleviation of disease symptoms associated with RGC loss. Furthermore, this approach also induced neurons with dopaminergic features in the striatum and alleviated motor defects in a Parkinson’s disease mouse model. Thus, glia-to-neuron conversion by CasRx-mediated Ptbp1 knockdown represents a promising in vivo genetic approach for treating a variety of disorders due to neuronal loss. [Display omitted] •Knockdown of Ptbp1 converts Müller glia into retinal ganglion cells in mature retinas•Central projections of converted retinal ganglion cells restore visual responses•Induction of neurons with dopaminergic features in PD model mice•Induced neurons alleviated motor dysfunctions in PD mice In vivo CasRx-mediated downregulation of a single RNA-binding protein, Ptbp1, locally converts glia to neurons and shows promise for treating disorders due to neuronal loss in mice.