Question

In humans, the huntingtin gene is essential for nerve cells to function effectively. People with Huntington’s disease have 2 different copies of the huntingtin gene – one normal and one mutated. The mutated huntingtin gene (HD) is caused by an excess of codons (CAG) that code for the amino acid glutamine. The HD gene is responsible for deterioration of the nerve cells, which leads to loss of one’s ability to move, feel and think.

Can you design an RNAi drug that targets only the HD gene and not the normal huntingtin gene?

Answer 1

Let's look at the scenario again a bit clearly -

People with Huntingtin disease have two copies (alleles) of the Huntingtin gene namely mutated Huntingtin allele (HD) and Normal allele (let's call it NHD).

The key to solve this question is the fact that mutated HD allele has excess of CAG codons than NHD allele. This means we can discriminate between the two alleles at the nucleotide level. Therefore we can design an RNAi drug ,with a siRNA, which selectively binds and silences the allele which has excess CAG codon repeats.

Note -

1) Overall idea of RNAi (RNA interference) drug is that a Small interfering RNA (siRNA) goes and binds with the mRNA of a particular gene and changes its activity (increase or decrease). Therefore, in the above example, we can design such siRNA which strategically discriminates between mutated HD allele and NHD allele (by complimentary base pairing priciple) on the basis of excessive presence of CAG codons and hence silences only the mutated HD allele and not the normal one.

2) It has been shown that such selective allele silencing can be achieved in the mouse in the case of Huntingtin disease. You can refer to the paper - "2012, Dongbo Yu et al, Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression" - for more details.