Gene Therapy for the Nervous System: Challenges and New Strategies

Abstract

Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain

“…Owing to the high sensitivity of neurons to chemical and biological insults and their poor accessibility for nonviral vectors, especially in vivo, targeting viruses with transduction of beneficial genes has been viewed as a promising therapeutic strategy. Yet, remaining conceptual and methodical challenges constrained applications of viral technologies to neurobiology research and preclinical studies, with their clinical use becoming available only recently [49,50]. One of the key objectives of AD therapy is protection of BFCNs and synapses from pathological insult, and restoration, or perhaps enhancement, of cholinergic functions [51][52][53].…”

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

“…Advanced research has shown that miRNAs are actively involved in the regeneration, regulation, and function of the central nervous system (88,89). Studies in C. elegans and cultured cell systems have shown that several distinct miRNAs are actively linked to neurodegenerative diseases, such as Parkinson's and Alzheimer's disease (90).…”

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

“…The current state of the art in using gene therapeutic approaches for the treatment of neurological disease is discussed in detail by Breakefield and colleagues in a separate review in this issue [118]. Gene therapy may be potentially applied to X-linked EDMD, in which emerin is not expressed in most cases.…”