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

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

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.

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Abbreviations

6-OHDA:

6-hydroxydopamine

Aβ:

Amyloid-β

AADC:

Amino acid decarboxylase

AAV:

Adeno-associated virus

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ApoE:

Apolipoprotein E

AQP:

Aquaporin

AV:

Adenoviral vector

BBB:

Blood-brain barrier

Bcl-w:

B-cell lymphoma-w

BDNF:

Brain-derived neurotrophic factor

BMVEC:

Brain microvascular endothelial cell

Cas9:

CRISPR-associated system 9

CMV:

Cytomegalovirus

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

CPF:

Chondroitin polymerizing factor

CRISPR:

Clustered regulatory interspaced short palindromic repeats

CS-1:

Chondroitin synthase-1

EAAT:

Excitatory amino acid transporter

EPO:

Erythropoietin

GALC:

Galactocerebrosidase

GDNF:

Glial cell-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

gfa2:

GFAP essential promoter segment

GFP:

Green fluorescent protein

GLAST:

Glutamate transporter

GS:

Glutamine synthase

h:

Human

HAND:

HIV-associated neurocognitive disorders

HD:

Huntington’s disease

HIV:

Human immunodeficiency virus

htt:

Huntingtin

ICV:

Intracerebroventricular

IGF:

Insulin-like growth factor

IL:

Interleukin

kb:

Kilobase

LCMV:

Lymphocytic choriomeningitis virus

LV:

Lentiviral vector

MBP:

Myelin basic protein

MS:

Multiple sclerosis

MCAO:

Middle cerebral artery occlusion

MHC:

Major histocompatibility complex

miRNA/miR/mi:

microRNA

muLV:

Murine leukemia virus

NAb:

Neutralizing antibody

NDDs:

Neurological diseases and disorders

Nef:

Negative regulatory factor

NGF:

Nerve growth factor

NHP:

Non-human primate

NMDA:

N-methyl-D-aspartate

NP:

Nanoparticle

NSE:

Neuron-specific enolase

NTRN:

Neurturin

PAMAM:

Polyamidoamine

PD:

Parkinson’s disease

pDNA:

Plasmid DNA

PDGF:

Platelet-derived growth factor

PEG:

Polyethylene glycol

PEI:

Polyethylenimine

PLGA:

Poly(lactic-co-glycolic) acid

RNAi:

RNA interference

scAAV:

Self-complementary AAV

ssAAV:

Single-stranded AAV

SCI:

Spinal cord injury

SD:

Sprague-Dawley

shRNA/sh:

Short hairpin RNA

siRNA/si:

Small interfering RNA

SN:

Substantia nigra

SVZ:

Subventricular zone

Syn:

Synapsin

TH:

Tyrosine hydroxylase

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

VSV-G:

Vesicular stomatitis virus-G

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Acknowledgements

The authors would like to acknowledge Ms. Kathleen Borgmann for her help with critical reading and scientific writing of the manuscript, tables, and figures. Ms. Lenore Price and Mr. Timothy Van Treuren proofread the manuscript. Dr. Irma Cisneros and Dr. Richa Pandey helped in making figures. The authors also thank all other members of Ghorpade laboratory at UNT Health Science Center and Labhasetwar laboratory at Cleveland Clinic for their help during the writing of the manuscript. National Institute of Neurological Disorders and Stroke (NINDS) awards R01 NS048837 to AG and R01 NS070896 to VL supported the presented work.

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Authors and Affiliations

  1. Institute for Molecular Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA

    Chaitanya R. Joshi & Anuja Ghorpade

  2. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Vinod Labhasetwar

  3. Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA

    Anuja Ghorpade

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  1. Chaitanya R. Joshi
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  2. Vinod Labhasetwar
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  3. Anuja Ghorpade
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Correspondence to Anuja Ghorpade.

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Joshi, C.R., Labhasetwar, V. & Ghorpade, A. Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery. J Neuroimmune Pharmacol 12, 51–83 (2017). https://doi.org/10.1007/s11481-016-9724-3

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