Huntington's disease clinical research

There are different therapies under investigation for Huntington's disease. Huntington's disease is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no cure or effective treatments. Animal models help in the ongoing investigations using intrabody therapy, gene silencing, or stem cell implants, but all are at their first steps. Several clinical trials of various compounds are also in development. Many of these trials use the unified Huntington's disease rating scale (UHDRS) developed by the Huntington's Study Group. This provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, backed up by a reference database of previous results provided by HSG for reference. Another avenue of research is understanding the physical mechanics of protein folding, HD is one of several targets of the folding@home project, one of the largest distributed computing systems on the World Wide Web.

Animal models
Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Neurochemically-induced mice or monkeys were first available, but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome, of mice (strain R6/2), ), Drosophila fruit flies, and more recently monkeys. Expression without insertion of a DNA repeat in nematode worms also produced a valuable model.

Intrabody therapy
Genetically-engineered intracellular antibody fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in Drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell. This therapy prevented larval and pupal mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan. Intrabodies have shown promise as a useful tool for drug discovery, and may potentially be used as a therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.

Gene silencing
As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT as a potential treatment. Using a mouse model, siRNA therapy achieved a 60% reduction in expression of mHTT and progression of the disease was stalled. However, this study used the human form of the mHTT protein in mice, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type mouse Htt gene expression unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of Htt is unknown, but in mice, complete deletion of the Htt gene is lethal. Thus, using RNA interference to treat HD could have unexpected effects unless knock-down of the normal Htt protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from shRNA over-expression. Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.

Stem cell treatments
Stem cell implants are a stem cell treatment where damaged neurons are replaced by transplantation of stem cells (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, embryonic stem cells can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons; if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but stem cell treatment for HD remains highly speculative and has not been tested in clinical trials.

Pharmacological
, several trials of various compounds are in development or ongoing, a few at the point of testing on larger numbers of people, known as phase III of clinical trials. Substances that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as creatine and CoQ10, the antibiotic Minocycline, antioxidant-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitors such as sertraline, fluoxetine, and paroxetine. In 2010, minocycline was found to be ineffective for humans in a multi-center trial.

A 2009 study suggested strong association between specific single nucleotide polymorphisms alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.

Other
Recently it was shown that increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.