Gene therapies for axonal neuropathies: Available strategies, successes to date, and what to target next

• Published in: Brain research 2020-04, Vol.1732, p.146683-146683, Article 146683
• Main Authors: Morelli, Kathryn H., Hatton, Courtney L., Harper, Scott Q., Burgess, Robert W.
• Format: Article
• Language: English
• Subjects: Animal models; Axon degeneration; Clinical trial; Gene therapy; Inherited peripheral neuropathy
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2020.146683

•We describe gene replacement, knockdown, and splicing gene therapy approaches.•We highlight successful gene therapy approaches for neuromuscular diseases.•We provide candidate disorders to be the next targets for gene therapy. Nearly one-hundred loci in the human genome have been associated with different forms of Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Despite this wealth of gene targets, treatment options are still extremely limited, and clear “druggable” pathways are not obvious for many of these mutations. However, recent advances in gene therapies are beginning to circumvent this challenge. Each type of CMT is a monogenic disorder, and the cellular targets are usually well-defined and typically include peripheral neurons or Schwann cells. In addition, the genetic mechanism is often also clear, with loss-of-function mutations requiring restoration of gene expression, and gain-of-function or dominant-negative mutations requiring silencing of the mutant allele. These factors combine to make CMT a good target for developing genetic therapies. Here we will review the state of relatively established gene therapy approaches, including viral vector-mediated gene replacement and antisense oligonucleotides for exon skipping, altering splicing, and gene knockdown. We will also describe earlier stage approaches for allele-specific knockdown and CRIPSR/Cas9 gene editing. We will next describe how these various approaches have been deployed in clinical and preclinical studies. Finally, we will evaluate various forms of CMT as candidates for gene therapy based on the current understanding of their genetics, cellular/tissue targets, validated animal models, and availability of patient populations and natural history data.