Cell-Based Delivery Approaches for DNA-Binding Domains to the Central Nervous System

Title:Cell-Based Delivery Approaches for DNA-Binding Domains to the Central Nervous System

Volume: 19 Issue: 12

Author(s): Peter Deng, Julian Halmai, Jennifer J. Waldo and Kyle D. Fink*

Affiliation:

• Department of Neurology, Stem Cell Program and Gene Therapy Center, UC Davis Medical Center, Sacramento, CA,United States

Keywords: DNA-binding domains, artificial transcription factors, zinc finger, CRISPR/Cas9, mesenchymal stem cell, Angelman syndrome, lipid nanoparticle, gene therapy.

Abstract: Advancements in programmable DNA-Binding Proteins (DBDs) that target the genome, such as zinc fingers, transcription activator-like effectors, and Cas9, have broadened drug target design beyond traditional protein substrates. Effective delivery methodologies remain a major barrier in targeting the central nervous system. Currently, adeno-associated virus is the most wellvalidated delivery system for the delivery of DBDs towards the central nervous with multiple, ongoing clinical trials. While effective in transducing neuronal cells, viral delivery systems for DBDs remain problematic due to inherent viral packaging limits or immune responses that hinder translational potential. Direct administration of DBDs or encapsulation in lipid nanoparticles may provide alternative means towards delivering gene therapies into the central nervous system. This review will evaluate the strengths and limitations of current DBD delivery strategies in vivo. Furthermore, this review will discuss the use of adult stem cells as a putative delivery vehicle for DBDs and the potential advantages that these systems have over previous methodologies.

Cite this article as:

Deng Peter , Halmai Julian , Waldo J. Jennifer and Fink D. Kyle *, Cell-Based Delivery Approaches for DNA-Binding Domains to the Central Nervous System, Current Neuropharmacology 2021; 19 (12) . https://dx.doi.org/10.2174/1570159X19666210517144044