Gene Therapy for Misfolding Protein Diseases of the Central Nervous System

Abstract

Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Accordingly, most recent studies aim to prevent protein misfolding and/or aggregation as a strategy to treat these pathologies. For instance, state-of-the-art approaches, such as silencing protein overexpression by means of RNA interference, are being tested with positive outcomes in preclinical models of animals overexpressing the corresponding protein. Therapies designed to treat central nervous system diseases should provide accurate delivery of the therapeutic agent and long-term or chronic expression by means of a nontoxic delivery vehicle. After several years of technical advances and optimization, gene therapy emerges as a promising approach able to fulfill those requirements. In this review we will summarize the latest improvements achieved in gene therapy for central nervous system diseases associated with protein misfolding (e.g., amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, Huntington's, and prion diseases), as well as the most recent approaches in this field to treat these pathologies.

Hsp104 Suppresses Polyglutamine-Induced Degeneration Post Onset in a Drosophila MJD/SCA3 Model

“…Indeed, gene therapy for neurodegenerative diseases remains in early developmental stages and considerable caution is essential at this time. However, initial studies have generated cautious optimism that gene therapy in the adult brain might be safe for various neurodegenerative disorders, including Parkinson's disease [84]–[88]. Thus, even though we await several key advances before any Hsp104 gene therapy (or any other gene therapy) becomes truly viable it is, nonetheless, important to develop solutions to protein misfolding and to test these solutions both in vitro and in the most appropriate animal models.…”

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

“…The main studied AAV serotypes are 2, 6, and 9, and while they share some features, they differ in others [69]. For instance, AAV2 is one of the first and most widely studied, but AAV9 is more widely implemented as a therapy due to its ability to cross the blood-brain barrier after intravenous administration.…”

“…For instance, AAV2 is one of the first and most widely studied, but AAV9 is more widely implemented as a therapy due to its ability to cross the blood-brain barrier after intravenous administration. AAV9 appears to transduce glial cells more than neurons, while AAV6 preferentially transduces neurons [69][70][71]. Due to their safety and efficacy, many AAV gene therapy clinical trials are ongoing as described at www.clinicaltrials.gov, namely phase I/II for SMA (NCT02122952), Parkinson's disease (NCT01973543, NCT00400634), Alzheimer's disease (NCT00087789), Duchenne muscular dystrophy (NCT00428935), and Leber congenital amaurosis (NCT00749957).…”

A reduction in the human adenovirus virion size through use of a shortened fibre protein does not enhance muscle transduction following systemic or localised delivery in mice

“…An enhancement in motor neuron uptake may be achieved through introduction of peptide motifs into the Ad capsid that specifically target infection to neurons (Poulin et al, 2011;Terashima et al, 2009), but this has yet to be examined. Alternatively, canine adenovirus has shown an enhanced ability to infect neurons and undergo retrograde transport (Soudais et al, 2001), suggesting it may be more amenable for the treatment of diseases of the motor neuron such as spinal muscular atrophy or amyotrophic lateral sclerosis (Goulet et al, 2013a;San Sebastian et al, 2013).…”