CureDRPLA is funding several research 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.
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.
Humanized ATN1 mouse
CureDRPLA worked with Taconic Biosciences to make a new humanized ATN1 mouse in which the entire ATN1 locus (including introns) are humanized and include a pure 112 CAG repeat in exon 5. Dr Jeff Carroll is managing this colony and he may be able to distribute these mice to both academic and commercial collaborators without licensing fees. In addition, CureDPRLA is working with Taconic Biosciences to make a line with a milder phenotype, which will have ~70 CAG repeats. We expect this line to be available from the summer of 2023.
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 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 reprogrammed some of these fibroblasts to iPSCs, which were used to differentiate into neurons.
Antisense Oligonucleotide Therapy for DRPLA
CureDRPLA funded 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 tested 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 investigated any amelioration of DRPLA hallmarks at histopathological and transcriptomic level. The results of this project are expected to be published in a scientific journal soon.
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 generated ASOs capable of knocking down human ATN1. The top ASO candidates are being further validated in patient-derived iPSCs to investigate whether the DRPLA phenotype in these cells can be reversed or prevented by ASO treatment. Furthermore, they are also investigating what role ATN1 plays in cells and if there are any side effects to reducing ATN1 levels.
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 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 several 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 has sites in the United Kingdom and the United States, which are currently recruiting participants:
- Paola Giunti – University College London (UK)
- Henry Houlden – University College London (UK)
- Yael Shiloh-Malawsky – University of North Carolina (USA)
- Claire Miller – NYU Grossman School of Medicine (USA)
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 is expected to be published soon.
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.
CureDRPLA Global Patient Registry
The CureDRPLA Global Patient Registry aims to collect data on up to as many DRPLA patients as possible to identify a well-characterized cohort for participation in retrospective and prospective research. Participants will be required to read and sign an IRB-approved informed consent document prior to accessing questionnaires within the Registry. The Registry will be available in English, French, Italian, Japanese, Korean, and Portuguese.
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.
CureDRPLA and Ataxia UK are the lead organizations behind this Registry. If you would like to find out more please contact the Registry Coordinator, Dr. Silvia Prades at firstname.lastname@example.org.