AUTHOR=Deng Peter , Halmai Julian A. N. M. , Beitnere Ulrika , Cameron David , Martinez Michele L. , Lee Charles C. , Waldo Jennifer J. , Thongphanh Krista , Adhikari Anna , Copping Nycole , Petkova Stela P. , Lee Ruth D. , Lock Samantha , Palomares Miranda , O’Geen Henriette , Carter Jasmine , Gonzalez Casiana E. , Buchanan Fiona K. B. , Anderson Johnathan D. , Fierro Fernando A. , Nolta Jan A. , Tarantal Alice F. , Silverman Jill L. , Segal David J. , Fink Kyle D. 

TITLE=An in vivo Cell-Based Delivery Platform for Zinc Finger Artificial Transcription Factors in Pre-clinical Animal Models

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 14 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.789913

DOI=10.3389/fnmol.2021.789913

ISSN=1662-5099

ABSTRACT=Zinc finger, transcription activator-like effectors, and CRISPR/Cas9 therapies to regulate gene expression are becoming viable strategies to treat genetic disorders, although effective in vivo delivery systems for these proteins remains a major translational hurdle. We describe the use of a mesenchymal stem/stromal cell (MSC)-based delivery system for the secretion of a zinc finger protein (ZF-MSC) in transgenic mouse models and young rhesus monkeys. Secreted ZF protein from mouse ZF-MSC was detectable within the hippocampus one week following intracranial or cisterna magna injection. Secreted ZF activated the imprinted paternal Ube3a in a transgenic reporter mouse and ameliorated motor deficits in a Ube3a deletion Angelman Syndrome mouse. Intrathecally administered autologous rhesus MSCs were well-tolerated for three weeks following administration and secreted ZF protein was detectable within the cerebrospinal fluid, midbrain, and spinal cord. This approach has the potential to provide a less-invasive means to deliver gene therapies into the central nervous system.