Gene Therapy for Neurological Disease: State of the Art and Opportunities for Next-generation Approaches. (10th May 2022)

• Record Type: Journal Article
• Authors: Morris, Gareth; Schorge, Stephanie
• Is Part Of: Neuroscience. Volume 490(2022)
• Page Start: 309
• Page End: 314
• Publication Date: 2022-05-10
• Subjects: gene therapy -- inducible promoters -- epilepsy -- microRNA -- genetic therapy; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2022.03.010
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Gene therapy is moving to clinical trials and showing enormous promise. New strategies can expand the number of conditions beyond 'genetic diseases'. The research focus is moving from proof of principle to widening the possible uses. Developing 'off switches' is a potential route to de-risking treatments. Another approach may use 'temporary' treatments test safety and a before permanent one. Abstract: Gene therapy for rare monogenetic neurological disorders is reaching clinics and offering hope to families affected by these diseases. There is also potential for gene therapy to offer new and effective treatments for common, non-genetic disorders. Treatments for Parkinson's Disease are in clinical trials, and treatments for refractory epilepsies are due to enter first-in-human clinical trials in 2022. Gene therapies for these disorders are based on delivering genes that address the mechanism of the disease, not repairing a mutated gene. Similar 'mechanistic' gene therapies could offer treatments to a wide range of neurological and neuropsychiatric diseases where there is a known mechanism that could be restored using gene therapy. However, the permanent nature of most gene therapies is a serious drawback for translation of gene therapies to a wide-range of diseases because it could present risk of irreversible adverse effects. Several lines of research are aimed at developing gene therapy approaches that allow for the treatment to be turned on and off, including: using proteins activated by exogenous ligands, and promoters turned on by activators. We review these approaches and propose an overall de-risking strategy for gene therapy for common neurological and psychiatric diseases. This approach is based on using a temporary mRNA-based treatment to initially assess efficacy and safety of the planned manipulation, and only following with permanent, virally-delivered treatment if the approach appears safe and effective.