RNAi: a potential new class of therapeutic for human genetic disease

Abstract

Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed.

Hereditary ataxias: overview

“…RNA interference strategies have been suggested for some autosomal dominant SCAs. 80 For further and up-to-date information, readers may search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.…”

The aggregation of mutant p53 produces prion-like properties in cancer

“…RNA interference (RNAi)-based systems modulate gene Prion volume 8 issue 1 expression at both transcriptional and posttranslational levels. 89 This latter method represents a very interesting strategy because it is highly specific (a desired characteristic in pharmacological drugs). 89 Such a strategy could be adopted for targets involving diseases caused by dominant gain-of-function mutations where the normal variant must be distinguished from the mutated form and where concentrations of the mutated protein in the cell must be decreased.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…These techniques target a highly specific sequence present in the mRNA of a target protein, leading to decreased translation (RNAi) or degradation of the mRNA transcript (RNAi/ASO) [84][85][86]. RNAi techniques can preferentially decrease the expression of a mutant allele over the wild-type transcript, as base pair mismatches between the siRNA and target RNA inhibit their binding and subsequent degradation [86]. Furthermore, these techniques allow for great versatility in the region targeted by these nucleotides, while retaining specificity due to unique mRNA sequences in the target transcripts.…”

“…Furthermore, these techniques allow for great versatility in the region targeted by these nucleotides, while retaining specificity due to unique mRNA sequences in the target transcripts. This form of treatment has been used in a mouse model of prion disease, and shRNA mediated knockdown of PrP in just a subset of neurons greatly extended the length of survival compared to control mice [82] While RNAi based systems show great promise in treating several diseases [84,86], limited uptake into cells and distribution to target tissues have hindered their use in vivo, and unforeseen off-target interactions may cause adverse effects in patients. Furthermore, high levels of shRNA appear to compete with endogenous miRNA processing, and have produced harmful effects in vivo [86].…”

“…This form of treatment has been used in a mouse model of prion disease, and shRNA mediated knockdown of PrP in just a subset of neurons greatly extended the length of survival compared to control mice [82] While RNAi based systems show great promise in treating several diseases [84,86], limited uptake into cells and distribution to target tissues have hindered their use in vivo, and unforeseen off-target interactions may cause adverse effects in patients. Furthermore, high levels of shRNA appear to compete with endogenous miRNA processing, and have produced harmful effects in vivo [86]. Developing viable strategies to facilitate the delivery of shRNA and siRNA, as well as improving their safety in vivo would greatly improve the therapeutic options available for numerous neurodegenerative diseases.…”