CureDRPLA is investing in a number of projects in hopes of rapidly developing novel therapeutics for DRPLA. Our primary motivation is time, and therefore we are working strategically with both academic and commercial partners to advance DRPLA treatments to the clinic as quickly as possible. A lay description of projects sponsored by CureDRPLA is provided below.
Preclinical projects are research projects that take place before clinical trials can begin. They aim to advance the diseases knowledge, for example finding and testing potential therapies in cell models and animal models.
DRPLA affected individuals have a CAG expansion in the Atrophin-1 (ATN1) gene, this mutation causes an abnormal ATN1 protein that will accumulate in the cells and will ultimately result in DRPLA (read more about DRPLA here). Our primary therapeutic modality of interest is to reduce the levels of ATN1 in patients.
- Dr. Ross at Weill Cornell Medicine has collected skin biopsies from 16 DRPLA patients. Her team has reprogrammed these skin cells into induced pluripotent stem cells (iPSCs), which means that these cells are now capable of developing into different cell types (e.g. brain cells – neurons). Patient-derived iPSCs will be used as a tool to understand and model DRPLA, and also to develop and test candidate drugs.
- Antisense therapy has emerged as an exciting and promising strategy for the treatment of various neurodegenerative disorders (i.e. spinal muscular atrophy, Duchenne muscular dystrophy). Antisense oligonucleotides (ASOs) can block the ability of a certain gene to make a protein. ASOs could prevent ATN1 protein aggregation in DRPLA, and therefore reverse or stop DRPLA progression. Dr. Giovanni Stevanin (Institut du Cerveau) and Dr. Manolis Fanto (King’s College London) are testing the efficacy of ASOs in human cell lines, including patient-derived iPSCs.
- Dr. Timothy Yu (Boston Children’s Hospital) and Dr. Vik Khurana (Harvard Medical School) are generating ASOs capable of reducing human ATN1 levels. The top ASO candidates will be further validated in patient-derived iPSCs to investigate whether the DRPLA phenotype in these cells can be reversed or prevented by ASO treatment.
- siRNA are small molecules that interfere with the expression of specific genes and prevent protein formation. DRPLA-specific siRNA could prevent ATN1 protein aggregation, and therefore reverse or stop DRPLA progression. Dr. Khvorova at University of Massachusetts is developing siRNA’s targeting ATN1.
- In addition, Ionis Pharmaceuticals has an advancing research program targeting ATN1 for the treatment of DRPLA. Ionis is working hard to evaluate molecules in hope of identifying a human candidate that could ultimately be advanced into the clinic over the next couple of years.
Understanding the Impact of DRPLA
CureDRPLA and Ataxia UK are working closely with the DRPLA community to gather more information about the impact of DRPLA on affected individuals, their relatives, and their caregivers. CureDRPLA engaged Casimir to conduct qualitative interviews with eight DRPLA caregivers and two patients to understand symptoms, natural history, impact on patient function and quality of life, and input on the outcomes that are important and relevant to them. Six caregivers reported findings from two or more family members resulting in descriptions from 19 affected individuals. The findings from these interviews will be published in spring 2021.
CureDRPLA and the National Ataxia Foundation organized an Externally-Led Patient Focused Drug Development (EL-PFDD) that allowed the Food and Drug Administration (FDA) in the United States to hear directly from patients, their families, caregivers, and patient advocates. The DRPLA community reported which symptoms matter the most to them, the impact the disease has on patient’s daily lives, and patient’s expectations of future treatments. You can access the replay here. NAF and CureDRPLA have prepared a report to summarise all the feedback gathered at this meeting. The report can be accessed here. Future applications for therapy approvals will use the report as a reference when evaluating the effectiveness of the treatment.
DRPLA Natural History and Biomarkers Study (DRPLA NHBS)
CureDRPLA and Ataxia UK are coordinating the DRPLA NHBS. This study will collect health information from DRPLA individuals over three years to understand how this condition develops over time. This project aims to characterize the natural history of DRPLA in both juvenile- and adult-onset patients. Participating in this study will involve annual appointments at the clinics where the neurologist will do some clinical assessments (e.g. ataxia scales, brain MRI, blood collection, etc.).
Biomarkers are biological molecules found in blood, other fluids, or tissues that are a sign of a normal or an abnormal process, and they can also reflect a disease state. This study also aims to identify genetic factors and biomarkers that could predict disease progression, and it will provide a platform to support the design and conduct of clinical trials in the future.
This study will have sites in the United Kingdom, the United States and Japan. These are the clinicians that will recruit patients to participate in this study:
Prof. Paola Giunti – University College London (UK)
Prof. Henry Houlden – University College London (UK)
Dr. Yael Shiloh-Malawsky – University of North Carolina (USA)
Dr. Heather Lau – NYU Grossman School of Medicine (USA)
Dr. Susan Perlman – UCLA Medical Center (USA)
Prof. Shoji Tsuji – University of Tokyo (Japan)
Prof. Hidehiro Mizusawa – National Centre of Neurology and Psychiatry (Japan)
Dr. Osamu Onodera – Niigata University (Japan)
Dr. Yukitoshi Takahashi – NHO Shizuoka Institute of Epilepsy and Neurological Disorders (Japan)
Dr. Masayuki Sasaki – National Centre of Neurology and Psychiatry (Japan)
Biosamples will also be collected from patients in other countries that cannot travel (or do not wish to travel) to a study site. If you would like to hear more about this study and find out if you could participate please contact Dr. Silvia Prades (email@example.com).
Information Sites and Support Groups
NIH – Genetics Home Reference
OMIM® – Online Mendelian Inheritance in Man
National Centre for Biotechnology-Gene Review
GARD – Genetic and Rare Diseases Information Centre
Cure Disease Kuri Channel
CureDRPLA Global Patient Registry
The CureDRPLA Global Patient Registry aims to collect data on up to as many DRPLA patients as possible. Participants will be asked to complete a set of questionnaires after enrollment with email requests for yearly updates. Data collected include participant demographic and contact information, details about diagnosis, functional mobility status, health economics, medical history, and activities of daily living.