There has been quite a buzz circulating about the possibility of therapeutic gene silencing strategies. Today I want to take a first look at what these therapies mean.

One great example where gene silencing could be used is in polyglutamine disorders. This includes several disorders where genes accumulate, by replication errors, a repeat expansion of the CAG codon (which codes for the amino acid glutamine, hence poly (=many) glutamines). A famous example of a polyglutamine disorder is Huntington’s disease. Why can these conditions be treated with gene silencing?

The answer is because the specific sequence on the mutant gene can be targeted by short mRNAs by two strategies. One strategy hijacks the RNAi pathway already present in the cell. RNAi stands for RNA-interference and is a natural process whereby gene expression is regulated by the presence of short double-stranded RNA molecules that match the sequence of the target gene to be suppressed (e.g. possibly silenced). Scientists can introduce their own short double-stranded mRNA molecules and utilize the RNAi machinery already present in the cell. An alternative is antisense oligonucleotides (AON), which also interfere with the translation and function of mRNA. Antisense means it is complimentary to an mRNA being targeted, and an oligonucleotide is a small stretch of nucleotides.

The middle portion of the above figure shows what happens when one copy of a gene (remember we have at least two copies of each gene) accumulates CAG repeats (shown as (CAG)ex). A mixture of normal and mutant proteins are produced (purple bubble), which can introduce a range of functional problems. Using RNAi or AON, the gene can be targeted in a non-allele specific manner, whereby the output in general is reduced (top panel), but mutant protein is still present. Alternatively, one may target the mutant allele specifically, whereby only protein from the normal allele is still produced (lower panel).

Its a lovely strategy in theory and has met with some success in mouse models of Huntington’s disease. However one major problem is that the mutant and normal alleles can be so similar that it is not possible to target only the mutant for silencing. Also, the gene product (protein) may still be functional and necessary and lead to adverse side effects if it’s too far silenced.

Clearly there are many outstanding questions, but polyglutamine disorders present themselves as strong candidates to test the usefulness of therapeutic gene silencing strategies. Keep a look out for future developments in this area.

Citation and image:

Scholefield, J., & Wood, M. (2010). Therapeutic gene silencing strategies for polyglutamine disorders Trends in Genetics, 26 (1), 29-38 DOI: 10.1016/j.tig.2009.11.005