RNA Interference used to inhibit Huntington's disease translation

RNA interference is used to prevent the expression of specific genes; hopefully, targeting unique rather than simply abundant sequences. The author’s objective in this article was to use RNA interference to suppress the CAG repeats in the Huntington’s gene that lead to the disease state. This research was initially discouraged as the siRNAs used to originally target genes showed little to no discrimination, as several genes were silenced instead of just the target. However; recent advances have allowed peptide nucleic acid antisense reagents to work with a much higher degree of selectivity than prior studies. The study compares the inhibition of the Huntington’s disease allele with the inhibition of the normal allele and other mRNA’s containing both CAG and CUG repeats.
This study showed that selectivity was not only great in the repeat targeting duplex but that this selectivity could even be further enhanced by specific mutations in which the binding efficiency was reduced. Further it was observed that different RNA duplexes silence gene production in different ways. Duplex 7, which had full complementarity to the mutant allele responsible for Huntington’s disease proved to be the most effective. The RNAi actually decreases the rate of transcription which decreases the prevalence of the mutant phenotype. Lastly the most interesting discovery was that an up-regulation of the wild type Huntington allele resulted when inhibition of the mutant occurred via duplex. This could be a result of the action of the RNAi itself, but most likely is a compensatory mechanism for the inhibition of one of the alleles. Basically in the heterozygote cases when a mutant allele is repressed or inhibited the wild type allele is transcribed, or translated, or both more frequently in order to compensate for the protein shortage. This provides some hope for, not just Huntington’s disease but treatment for any disease caused by an expansion of a repeated three gene sequence in the near future. In conclusion the recent advances in the field have taken a technique that was previously disregarded as too hazardous to a patient’s health and begun to evolve into a specific and targeted technique with the promise of one day treating a series of genetic disorders.
I chose this article because I plan to have a future in drug research and it proposed a treatment for a genetic disease. The entire article was interesting as I did not have much in the way of prior knowledge of RNA interference at all. Further I find it somewhat incredible that RNA, the component use for translation, can also be an inhibitor of the very action the text book teaches as almost its’ sole purpose. Lastly it was interesting to see that even at the DNA level the human body does attempt to compensate whenever it is obstructed, especially in this case. Shutting down or restricting mutant alleles will actually cause the other allele to become more pronounced has huge implications if it applies to more than just this set of genes.

J Harper.