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. The safety of RNA interference, and allele-specific oligonucleotide (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain. 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 humans with HD 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. A phase 3 trial of this compound, renamed tominersen and sponsored by Roche Pharmaceuticals, began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable. A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced. Gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9. Increasing huntingtin clearance Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it. As mHtt (and many other protein aggregates) are degraded by autophagy, increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease. Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity. Improving cell survival Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses. Neuronal replacement Stem-cell therapy is used to replace damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results. Whatever their future therapeutic