Frontiers in Molecular Neuroscience (Jan 2022)
An in vivo Cell-Based Delivery Platform for Zinc Finger Artificial Transcription Factors in Pre-clinical Animal Models
- Peter Deng,
- Peter Deng,
- Peter Deng,
- Peter Deng,
- Julian A. N. M. Halmai,
- Julian A. N. M. Halmai,
- Julian A. N. M. Halmai,
- Ulrika Beitnere,
- David Cameron,
- David Cameron,
- David Cameron,
- Michele L. Martinez,
- Charles C. Lee,
- Jennifer J. Waldo,
- Jennifer J. Waldo,
- Jennifer J. Waldo,
- Krista Thongphanh,
- Krista Thongphanh,
- Anna Adhikari,
- Nycole Copping,
- Stela P. Petkova,
- Ruth D. Lee,
- Samantha Lock,
- Samantha Lock,
- Samantha Lock,
- Miranda Palomares,
- Henriette O’Geen,
- Jasmine Carter,
- Jasmine Carter,
- Jasmine Carter,
- Casiana E. Gonzalez,
- Casiana E. Gonzalez,
- Casiana E. Gonzalez,
- Fiona K. B. Buchanan,
- Fiona K. B. Buchanan,
- Fiona K. B. Buchanan,
- Johnathan D. Anderson,
- Fernando A. Fierro,
- Jan A. Nolta,
- Alice F. Tarantal,
- Jill L. Silverman,
- David J. Segal,
- Kyle D. Fink,
- Kyle D. Fink,
- Kyle D. Fink
Affiliations
- Peter Deng
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Peter Deng
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Peter Deng
- Department of Biochemistry and Molecular Medicine, Genome Center, University of California, Davis, Davis, CA, United States
- Peter Deng
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Julian A. N. M. Halmai
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Julian A. N. M. Halmai
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Julian A. N. M. Halmai
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Ulrika Beitnere
- Department of Biochemistry and Molecular Medicine, Genome Center, University of California, Davis, Davis, CA, United States
- David Cameron
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- David Cameron
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- David Cameron
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Michele L. Martinez
- Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, Gene Therapy Center, and California National Primate Research Center, University of California, Davis, Davis, CA, United States
- Charles C. Lee
- Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, Gene Therapy Center, and California National Primate Research Center, University of California, Davis, Davis, CA, United States
- Jennifer J. Waldo
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Jennifer J. Waldo
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Jennifer J. Waldo
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Krista Thongphanh
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Krista Thongphanh
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Anna Adhikari
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Nycole Copping
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Stela P. Petkova
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Ruth D. Lee
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Samantha Lock
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Samantha Lock
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Samantha Lock
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Miranda Palomares
- Department of Biochemistry and Molecular Medicine, Genome Center, University of California, Davis, Davis, CA, United States
- Henriette O’Geen
- Department of Biochemistry and Molecular Medicine, Genome Center, University of California, Davis, Davis, CA, United States
- Jasmine Carter
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Jasmine Carter
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Jasmine Carter
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Casiana E. Gonzalez
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Casiana E. Gonzalez
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Casiana E. Gonzalez
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Fiona K. B. Buchanan
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Fiona K. B. Buchanan
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Fiona K. B. Buchanan
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- Johnathan D. Anderson
- Department of Otolaryngology, University of California, Davis, Davis, CA, United States
- Fernando A. Fierro
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Jan A. Nolta
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Alice F. Tarantal
- Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, Gene Therapy Center, and California National Primate Research Center, University of California, Davis, Davis, CA, United States
- Jill L. Silverman
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- David J. Segal
- Department of Biochemistry and Molecular Medicine, Genome Center, University of California, Davis, Davis, CA, United States
- Kyle D. Fink
- Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, United States
- Kyle D. Fink
- Stem Cell Program and Gene Therapy Center, University of California, Davis, Sacramento, CA, United States
- Kyle D. Fink
- Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, United States
- DOI
- https://doi.org/10.3389/fnmol.2021.789913
- Journal volume & issue
-
Vol. 14
Abstract
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 in vivo 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 Ube3a in a transgenic reporter mouse and ameliorated motor deficits in a Ube3a 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.
Keywords
- zinc finger
- Angelman Syndrome (AS)
- mesenchymal stem/stromal cell
- artificial transcription factor (ATF)
- cell-based delivery
