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

Hum Genet. 2011 Nov;130(5):583-605. doi: 10.1007/s00439-011-0995-8. Epub 2011 May 3.


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.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / therapy
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / therapy
  • Anemia, Sickle Cell / drug therapy
  • Anemia, Sickle Cell / genetics
  • Anemia, Sickle Cell / therapy
  • Animals
  • Clinical Trials as Topic
  • Genes, Dominant
  • Genetic Diseases, Inborn / drug therapy
  • Genetic Diseases, Inborn / therapy*
  • Genetic Therapy / methods*
  • Humans
  • Huntington Disease / drug therapy
  • Huntington Disease / genetics
  • Huntington Disease / therapy
  • Mice
  • Molecular Targeted Therapy*
  • Muscular Dystrophies / drug therapy
  • Muscular Dystrophies / genetics
  • Muscular Dystrophies / therapy
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / therapy
  • Parkinson Disease / drug therapy
  • Parkinson Disease / genetics
  • Parkinson Disease / therapy
  • Point Mutation
  • RNA Interference*
  • Rats
  • Spinocerebellar Ataxias / drug therapy
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / therapy