HCR.20.069 – TRASH-Q: Patient-Tailored Reduction of Aggregation-prone proteins to Stop Hereditary neurodegenerative polyglutamine (Q) diseases

Route: Health care research, sickness prevention and treatment

Cluster question: 098 How can we use breakthroughs in basic biomedical research to develop new medicines?

Huntington’s disease (HD) and various ADCA/SCA ataxias are inherited neurodegenerative disorders caused by a polyGlutamine (polyQ) expansion in the disease-related protein leading to protein aggregation and neurodegeneration. Strategies to lower these proteins by either RNA-targeting or by improving their degradation should delay, halt or prevent disease. Recent breakthroughs include two RNA-targeting therapy trails aiming to lower synthesis (including Dutch UMCs and biotech companies) as well as the identification of key enzymes involved in the degradation of the disease-related protein, which allows drug screens to identify small molecule compounds improving selective protein turnover.

Exploration of these developments are however limited by the variety of HD phenotypes due to polyQ expansion repeats including juvenile forms of HD, the gap between commonly used small animal models with extreme mutations, the limitations of invasive RNA-targeting approaches, the limited attention for polyQ-related treatment and research technologies in student teaching programs, and the taboo on HD resulting in only 10-15% of people at risk to take a genetic test or consider IVF treatment.

We will combine the efforts of Dutch polyQ researchers and professionals in academia with biotech, patient foundations and expertise centers to expand polyQ lowering strategies including small molecule compound studies to improve selective protein homeostasis, to develop and upscale patient-derived isogenic cell-lines instead of animal models to use for research and validation, and recruit HD and ADCA families as donor and to participate in studies. We also aim to generate methodologies and biomarkers for pediatric forms in order to include them in the new therapeutic studies towards pediatric forms of HD, define a better correlation between CAG repeat size, effects of CAA interruptions, and age-of-onset and progression of disease, and to define patient-specific ‘molecular phenotypes’ to personalize current strategies for treatment including juvenile forms of HD but also for better physiotherapy and support

Keywords

Huntingtin lowering, Huntington's Disease, Neurodegeneration, patient-derived cell lines

Submitter

Organisation AmsterdamUMC
Name Prof. dr. E.A.J. (Eric) Reits
E-mail e.a.reits@amsterdamumc.nl
Website https://www.medischebiologie.nl/reits-group/