Abstract: Provided herein are Class 2 Type V CRISPR systems comprising CRISPR-Cas polypeptides, (e.g., CasX:gRNA systems comprising CasX polypeptides), guide nucleic acids (gRNA), and optionally donor template nucleic acids, useful in the modification of a PTBP1 gene. The systems are also useful in methods for reprogramming certain eukaryotic cells into functional neurons by the knocking down or knocking out the PTBP1 gene in those cells. Also provided are methods of using such systems in methods of treatment of a subject with a PTBP1-related disease.