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.
