Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

Chaitanya R. Joshi, Vinod Labhasetwar, Anuja Ghorpade

Research output: Contribution to journalReview article

17 Citations (Scopus)

Abstract

Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of a ideal cellular target(s), available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability and most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in the context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles are discussed from the perspective of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analyses of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

Original languageEnglish
Pages (from-to)51-83
Number of pages33
JournalJournal of Neuroimmune Pharmacology
Volume12
Issue number1
DOIs
StatePublished - 1 Mar 2017

Fingerprint

Genetic Therapy
Brain
Genes
Central Nervous System
Clinical Trials
Nervous System Diseases
Nanoparticles
Therapeutics
RNA Editing
RNA Interference
Blood-Brain Barrier
Pharmacology
Technology
Phenotype
Gene Expression
Pharmaceutical Preparations

Keywords

  • Adeno-associated viral vectors
  • Adenoviral vectors
  • CNS-gene delivery
  • CNS-specific promoters
  • Lentiviral vectors
  • Polymeric nanoparticles

Cite this

Joshi, Chaitanya R. ; Labhasetwar, Vinod ; Ghorpade, Anuja. / Destination Brain : the Past, Present, and Future of Therapeutic Gene Delivery. In: Journal of Neuroimmune Pharmacology. 2017 ; Vol. 12, No. 1. pp. 51-83.
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Destination Brain : the Past, Present, and Future of Therapeutic Gene Delivery. / Joshi, Chaitanya R.; Labhasetwar, Vinod; Ghorpade, Anuja.

In: Journal of Neuroimmune Pharmacology, Vol. 12, No. 1, 01.03.2017, p. 51-83.

Research output: Contribution to journalReview article

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T2 - the Past, Present, and Future of Therapeutic Gene Delivery

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AU - Ghorpade, Anuja

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N2 - Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of a ideal cellular target(s), available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability and most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in the context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles are discussed from the perspective of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analyses of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

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