Therapy for Dominant Inherited Diseases by Allele-Specific RNA Interference: Successes and Pitfalls
RNA interference (RNAi) is a conserved mechanism for post-transcriptional
gene silencing mediated by messenger RNA (mRNA) degradation. RNAi is commonly
induced by synthetic siRNA or shRNA which recognizes the targeted mRNA by base
pairing and leads to target-mRNA degradation. RNAi may discriminate between two
sequences only differing by one nucleotide conferring a high specificity of RNAi for its
target mRNA. This property was used to develop a particular therapeutic strategy
called “allele-specific-RNA interference” devoted to silence the mutated allele of genes causing dominant inherited diseases
without affecting the normal allele. Therapeutic benefit was now demonstrated in cells from patients and animal
models, and promising results of the first phase Ib clinical trial using siRNA-based allele-specific therapy were reported in
Pachyonychia Congenita, an inherited skin disorder due to dominant mutations in the Keratin 6 gene. Our purpose is to
review the successes of this strategy aiming to treat dominant inherited diseases and to highlight the pitfalls to avoid.
Keywords: Allele-specific silencing, Dominant inherited diseases, Pitfalls, RNA interference, Single nucleotide substitution, Gene-based therapy.
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