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

Peter Deng, Julian Halmai, Jennifer J. Waldo, Kyle D. Fink

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2125-2140
Number of pages16
JournalCurrent Neuropharmacology
Issue number12
StatePublished - 2021
Externally publishedYes


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

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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