 Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHTT is reduced, symptoms improve. Safety of non-allele specific RNAi and ASO gene silencing has now been demonstrated in mice and the large, human-like brains of primates. Allele-specific silencing attempts to silence mutant HTT while leaving wild-type HTT untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele. The first 'gene silencing' trial involving human HD patients began in 2015, testing the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology. Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntington's disease mutation-carriers in 2015 using a novel' single-molecule counting ' immunoassay, providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.
