Gene therapy for neurological disorders

ABSTRACT

Introduction: Many nervous system disorders are minimally responsive to existing treatments but they are potential candidates for gene therapy, an approach that can correct the genetic abnormalities contributing to its pathogenesis at molecular level. Gene therapy involves either the introduction of a replacement allele into cells to compensate for loss of gene function or the silencing of dominant mutant allele that is pathologic to cells.

Areas covered: This review discusses the currently available gene therapy techniques, potential problems derived from gene therapy strategies and the recent development of gene therapy to treat neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and strokes.

Expert opinion: Gene therapy may revolutionize the treatment of neurological disorders in the coming decades but there are still great challenges ahead. The strength of gene therapy has been emphasized in the overexpression of therapeutic genes. However, in a number of dominantly inherited nervous system diseases, the ideal therapeutic goal would be to inhibit the expression of disease-causing allele. Gene silencing strategies by single-stranded antisense oligonucleotides and RNA interference represent a major breakthrough. Clinical trials using these approaches for dominant diseases are likely to be implemented in the near future.

KEYWORDS:

• Alzheimer’s disease
• amyotrophic lateral sclerosis
• Gene therapy
• Huntington’s disease
• Parkinson’s disease
• stroke

Article highlights

• Direct modulation of the Aβ trafficking pathway and non-Aβ-targeted approaches herald a new therapeutic frontier for AD.

• Four candidates for PD gene therapy including EIAV-AADC-TH-GCH, AAV2-AADC, AAV2-GAD and AAV2-Neurturin are currently under clinical trial evaluation.

• Potential efficacy of viral vector-mediated RNAi in targeting the suppression of dominant disease genes has shed new lights on the gene therapy for dominantly inherited diseases, including ALS and HD.

• Gene transfer approach for stroke targets prevention of vasospasm after subarachnoid hemorrhage, ischemia-induced apoptosis, inflammation and derangement of neurovascular units.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.