Not all dances are beautiful and graceful. There is, in fact, a condition that leads individuals to uncontrollably "dance," resulting in terrible physical and mental impairment.

This disease is known as Huntington's disease (HD), named after the physician who first characterized it in 1872. HD affects people during their middle to late years all around the world. HD is a rare, autosomal dominant degenerative disease of the basal ganglia and cerebral cortex. The symptoms of Huntington's disease can vary widely depending on the individual, but often include involuntary movements, cognitive impairment, and emotional disturbances. As the disease progresses, individuals may experience difficulty with speech, swallowing, and mobility, ultimately leading to complete dependence on caregivers. Sadly, there is no effective treatment or medication to stop or reverse HD, and several commercially available pharmaceuticals are utilized merely to relieve motor symptoms rather than to achieve a fundamental treatment.

The pathological mechanism of HD

Among HD patients, the caudate putamen and nucleus accumbens in particular experience atrophy and neuronal loss. A mutation in the huntingtin gene (HTT), which produces the huntingtin protein, causes this disease. Towards the 5' end of the coding region of this gene, there is a polymorphic region of CAG repeats. When the number of CAG repeats rises above 40, it is considered abnormal and leads to polyQ amplification, which causes HTT protein to misfold. These fragments interact incorrectly with a wide range of proteins and aggregate in the nuclei and nerve terminals of neurons, resulting in nerve cell injury in multiple brain regions^[1].

Huntingtin mutation and basal ganglia^[2]

While HD has been under intensive investigation since 1993, there is currently no viable medication to halt the disease's progression. Nevertheless, there are reasons to be optimistic about the future.

Therapeutic research and development for HD

Gene therapy is shedding new light on the condition of HD patients. Gene therapy involves the insertion of a normal huntingtin gene into cells to replace the faulty one. This approach has shown some success in animal models and is currently being tested in clinical trials. For example, UniQure disclosed data on its investigational gene therapy AMT-130, which was well-tolerated after 12 months of administration in a phase I/II clinical trial's low-dose group. There were no significant safety issues, and patients' mutant Huntington protein (mHTT) levels in their CSF decreased by an average of 53.8%. Perhaps this treatment will be the first of its kind to slow or stop the progression of HD.

Another direction of HD research is the application of stem cells to replace damaged neurons in the brain. While this is still a relatively new field, early studies suggest that stem cell therapy may hold promise for the treatment of HD and other neurodegenerative disorders.

HD is a horrible condition that impacts not only the sufferer but also their family and loved ones. While there is presently no effective treatment to reverse disease development, gene therapy shows great promise for changing the disease's course. With continued advances in medical science and a growing community of support, we can work towards a future where Huntington's disease is no longer a source of suffering and despair.

What GemPharmatech can do for you 

The lack of effective drugs to combat Huntington's disease is a challenge. An important aspect of drug development is selecting the appropriate animal models. In this regard, mouse models offer several advantages for HD research, including comprehensive research tools and genetic and phenotypic similarity to patients.

GemPharmatech has developed the B6-hHTT130-N model, which holds independent IP. This model carries a human HTT gene fragment with 130 CAG repeats. The B6-hHTT130-N model has been shown to exhibit significant motor function abnormalities at 17 weeks, simulating the pathological and motor function phenotypes of HD. The model can be used for drug screening and safety evaluation in HD therapy. Additionally, the model has a survival period of over 24 weeks, which is longer than the classical R6/2 model, making it more suitable for studying age-dependent effects and providing a longer window for preclinical evaluation.

Reference:

1. Nance MA. Genetics of Huntington disease. Handb Clin Neurol. 2017;144:3-14.

2. Aguiar, S., van der Gaag, B. & Cortese, F.A.B. RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA. Transl Neurodegener 6, 30 (2017).