Possibility 2: trigger methylation to suppress or silence a gene. Methylation-dependent gene
silencing is the canonical role of cytosine methylation in development, and capitalizing on this
mechanism for therapeutic benefit would be quite powerful. This might be especially applicable
to diseases mediated by a gain-of-function mutation of a single allele of a gene. An example of a
potential theoretical application of this type of approach is Huntington’s disease (HD). Mutant
huntingtin (HTT) protein causes HD, which is likely mediated by a gain of function of the mutant
gene. Silencing mutant HTT expression using cytosine methylation of the mutated allele could
potentially lead to a treatment or even cure for HD. Yu et al. (106) used a conceptually similar
but small interfering RNA–based approach to achieve allele-specific knockdown of mutant HTT
in a mouse model, with therapeutic benefit demonstrated as a result.