Gene Therapy Options as New Treatment for Inherited Peripheral Neuropathy

Abstract

Inherited peripheral neuropathy (IPN) is caused by heterogeneous genetic mutations in more than 100 genes. So far, several treatment options for IPN have been developed and clinically evaluated using small molecules. However, gene therapy-based therapeutic strategies have not been aggressively investigated, likely due to the complexities of inheritance in IPN. Indeed, because the majority of the causative mutations of IPN lead to gainof-function rather than loss-of-function, developing a therapeutic strategy is more difficult, especially considering gene therapy for genetic diseases began with the simple idea of replacing a defective gene with a functional copy. Recent advances in gene manipulation technology have brought novel approaches to gene therapy and its clinical application for IPN treatment. For example, in addition to the classically used gene replacement for mutant genes in recessively inherited IPN, other techniques including gene addition to modify the disease phenotype, modulations of target gene expression, and techniques to edit mutant genes have been developed and evaluated as potent therapeutic strategies for dominantly inherited IPN. In this review, the current status of gene therapy for IPN and future perspectives will be discussed.

Myelin Biology

“…In conclusion, the generation and characterization of animal models for these neuropathies as well as the increasing number of IPN genes identified using NGS (next generation sequencing) technologies has enormously contributed to expand and deep our knowledge on myelin biology. In turn, the knowledge of the underlying pathogenetic mechanisms allowed to design and validate at the preclinical level promising therapeutical approaches, which can be potentially translated to human in a near future [129][130][131][132][133].…”

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

“…These are all short RNA sequences (up to 22 nucleotides long) that complimentarily bind on their target mRNA, aiming to mediate degradation or block translation. 72,73 ONPATTRO (Patisiran) by Alnylam Pharmaceuticals ® is the first Food and Drug Administration (FDA)-approved siRNA-mediated silencing drug and is used to treat hereditary transthyretin mediated amyloidosis (hATTR) (NCT01960348). [74][75][76][77][78][79] ASOs are artificial, short (up to 50 nucleotides long), oligodeoxynucleotides that complimentarily bind to their mRNA target and promote its degradation, ultimately leading to gene silencing.…”

“…The RNAi family includes siRNAs, short hairpin RNAs (shRNAs), and micro‐RNAs (miRs). These are all short RNA sequences (up to 22 nucleotides long) that complimentarily bind on their target mRNA, aiming to mediate degradation or block translation 72,73 . ONPATTRO (Patisiran) by Alnylam Pharmaceuticals® is the first Food and Drug Administration (FDA)‐approved siRNA‐mediated silencing drug and is used to treat hereditary transthyretin mediated amyloidosis (hATTR) (NCT01960348) 74–79 …”

Nanotechnology for cardiovascular diseases

“… 208 However, the clinical translation of siRNA therapeutics has been limited by several factors, including cytotoxicity, nuclease degradation and off-target effects, in recent years. 209 Benefiting from recent studies of the high targeting and stability of multifunctional nanocarriers in circulation, siRNA nanomedicines could rapidly penetrate disrupted plaque endothelial barriers and downregulate the expression of target genes locally, attenuating plaque inflammation in lesions. 210 The recruitment of arterial leukocytes triggered by adhesion molecules is one of the key points in the progression of atherosclerosis.…”