Novel therapeutic pathway and Hong Kong patient registry set out to spur Huntington’s disease insights

3 August 2021

In an international research collaboration involving scientists from the Chinese University of Hong Kong (CUHK), including Professor Edwin Chan Ho-yin (Croucher Scholarship 1996) from the School of Life Sciences, researchers have provided further insight into the development of Huntingdon’s disease and offered fresh hope for new therapeutic directions for sufferers.

Chan is also establishing a Huntingdon’s disease patient registry for Hong Kong, with the aim to support long-term clinical care of patients and to facilitate translational biomedical research.

Huntington’s disease is a rare inherited disorder that usually starts to affect adults in their mid-thirties or forties and causes a progressive breakdown of nerve cells in the brain. Symptoms include involuntary movements, poor coordination, and decline in cognitive thinking ability. There is currently no cure for the disease, with medication only available to manage symptoms.

The international scientific team found that a special RNA species called small CAG repeat RNAs (sCAG) plays a destructive role in the pathogenesis of Huntingdon’s by causing damage to the genetic materials in the genome.

Researchers showed that when sCAG accumulates in nerve cells at a high enough level, the normal function of NUDT16, an important factor responsible for safeguarding the integrity of genetic materials in the genome, is compromised. This results in rapid accumulation of genome damage in brain cells and eventually triggers neuronal degeneration and cell death.

The study, carried out together with the University of Illinois at Urbana-Champaign, US, and the University of Pisa, Italy, is the first to demonstrate sCAG can induce neuronal DNA damage. The findings have been published in the Proceedings of the National Academy of Sciences of the USA.

In addition, restoring the normal function of NUDT16 can rescue DNA damage and apoptosis – a form of cell death – in Huntington’s disease models. And using nuclear magnetic resonance spectroscopy, the team discovered a small molecule compound, known as DB213, can restore motor deficits in mice that contract the disease.

This is now providing a basis for the team to further modify the compound for achieving higher therapeutic effects against Huntingdon’s.

Chan said of tests with DB213 on primary neurons and mouse models: “We are happy to see that this compound can go to the brain by itself when applied through the nostrils, further highlighting its therapeutic potential. We are now ready to bring this study to the preclinical stage. Other than Huntingdon’s disease, our compound can also be utilised in several types of spinocerebellar ataxias, another group of rare neurological diseases.”

Meanwhile, a key goal of the Hong Kong patient registry is to prepare the city to join the Enroll-HD programme, a global observational study for Huntingdon disease families that provides new drug clinical trials opportunities for patients worldwide.

Edwin Chan Ho-yin is Professor and Associate Director of the Biochemistry Programme at the School of Life Sciences, Chinese University of Hong Kong (CUHK), among other roles at the university. Chan received his undergraduate training in biochemistry at CUHK. He undertook doctoral studies in genetics at the University of Cambridge, UK, and postdoctoral research in neuroscience at the University of Pennsylvania, US. He has been investigating rare neurological and neuromuscular disorders for over 20 years. In 2014, he established an intercontinental research collaboration network on rare neuronal diseases, including amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, myotonic dystrophy, and spinocerebellar ataxias. He is a Founding Member and Executive Committee member of the Young Academy of Sciences of Hong Kong. Chan was awarded a Croucher Scholarship in 1996.

To view Professor Chan’s Croucher profile, please click here