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. Our primary therapeutic modality of interest is ATN1-lowering, though we remain optimistic that druggable pathways involved in multiple neurodegenerative diseases – notably somatic instability of CAG tracts – may provide fruitful for DRPLA therapeutics. A rough description of projects sponsored by CureDRPLA is provided below.

Funding Opportunities

CureDRPLA provides funding for innovative and relevant research on DRPLA. We accept applications all year round. Please contact us if you have a research proposal and we will send you information about the application process.

Preclinical Projects

Humanized ATN1 mouse

CureDRPLA is working with Taconic Biosciences to make a new humanized ATN1 mouse in which the entire ATN1 locus (including introns) are humanized and include a pure 100 CAG repeat in exon 5. We will be able to distribute these mice to both academic and commercial collaborators without licensing fees. We anticipate having a large number of heterozygous mice for research studies in late June, 2021.

DRPLA Biomarkers Development

We are pursuing both disease progression and pharmacodynamic biomarker assays in DRPLA.   As part of the DRPLA Natural History and Biomarkers Study, participating sites will collect a number of biomaterials (including plasma and cerebrospinal fluid) to develop biomarkers for this condition.”

Induced Pluripotent Stem Cells Repository

CureDRPLA has engaged Dr. M. Elizabeth Ross at the Center for Neurogenetics at Weill Cornell Medicine to create an in vitro model derived from DRPLA patient cells that will be used for evaluating the efficacy of various antisense oligonucleotides (ASOs) and/or small biomolecules to reverse the aberrant cellular features associated with patient mutations. They have fibroblast cultures from 16 DRPLA patients, and they are reprogramming some of these fibroblasts to iPSCs, which will be used to differentiate into neurons.

Antisense Oligonucleotide Therapy for DRPLA

CureDRPLA is funding a project lead by Dr. Giovanni Stevanin (Institut du Cerveau) and Dr. Manolis Fanto (King’s College London) to develop a study of efficacy of ASOs in human cell lines. In partnership with Ionis Pharmaceuticals, these researchers are testing ASOs in a collection of human DRPLA fibroblasts to test the applicability of ASOs to a wide spectrum of patients and for effectiveness of ATN1 downregulation. They are investigating any amelioration of DRPLA hallmarks at histopathological and transcriptomic level.

CureDRPLA has engaged Dr. Timothy Yu (Boston Children’s Hospital) and Dr. Vik Khurana (Harvard Medical School) to characterize a robust and experimentally manipulatable cell line for use in high throughput drug screening. Yu and Khurana groups will generate ASOs capable of knocking down human ATN1. 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.

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.

siRNA for Treatment of DRPLA

CureDRPLA has engaged the group of Dr. Khvorova at University of Massachusetts to develop divalent siRNA’s targeting ATN1. Given the widespread and long-term brain delivery provided by divalent siRNA in mice and non-human primates (PMID: 31375812), we envision this as a tool molecule for ATN1 lowering experiments both in vitro and in vivo. The target sequence is 100% conserved between mouse and human, facilitating translational experiments.

DRPLA Natural History and Biomarkers Study (DRPLA NHBS)

CureDRPLA and Ataxia UK are coordinating the DRPLA NHBS. This project aims to characterize the natural history of DRPLA in both juvenile- and adult-onset patients and study different modalities of biomarkers in this condition. In addition, this study 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 is a prospective multicenter study. Participants will complete an annual visit for three years and will be asked to complete a number of clinical assessments, brain MRI, and biosample collection. This protocol includes scales and questionnaires that are crucial to capture the progression of the disease in its multi-systemic aspects and instruct future trial design.

This study will have sites in the United Kingdom, the United States and Japan. Primary investigators participating in this project:

• Prof. Paola Giunti – University College London (UK)
• Prof. Henry Houlden – University College London (UK)
• Dr. Yael Shiloh-Malawsky – University of North Carolina (USA)
• Dr. Claire Miller – 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 please contact Dr. Silvia Prades (spradesabadias@ataxia.org.uk).

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 adult 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. A manuscript with the findings from these interviews is under preparation and it 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 FDA 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 wishes for future treatments. You can access the replay here. NAF and CureDRPLA are preparing The Voice of the Patient Report to summarise all the feedback gathered at this meeting. Once ready, this report will be submitted to the FDA and will be published here. Future applications for therapy approvals will use the report as a reference when evaluating the effectiveness of the treatment.