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=14

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=<p>Zinc finger (ZF), transcription activator-like effectors (TALE), and CRISPR/Cas9 therapies to regulate gene expression are becoming viable strategies to treat genetic disorders, although effective <italic>in vivo</italic> delivery systems for these proteins remain a major translational hurdle. We describe the use of a mesenchymal stem/stromal cell (MSC)-based delivery system for the secretion of a ZF protein (ZF-MSC) in transgenic mouse models and young rhesus monkeys. Secreted ZF protein from mouse ZF-MSC was detectable within the hippocampus 1 week following intracranial or cisterna magna (CM) injection. Secreted ZF activated the imprinted paternal <italic>Ube3a</italic> in a transgenic reporter mouse and ameliorated motor deficits in a <italic>Ube3a</italic> deletion Angelman Syndrome (AS) mouse. Intrathecally administered autologous rhesus MSCs were well-tolerated for 3 weeks following administration and secreted ZF protein was detectable within the cerebrospinal fluid (CSF), midbrain, and spinal cord. This approach is less invasive when compared to direct intracranial injection which requires a surgical procedure.</p>