RFC1: a global multicenter multimodal natural history, clinical outcome and biomarker study, based on the ARCA registry

Goal:
- Chart the prospective feature evolution and longitudinal natural history of RFC1 disease

Description:
Following their recent discovery, repeat expansions in RFC1 are already by now appreciated as one of the most frequent causes of recessive ataxia worldwide, thus presenting a major novel disease target for highly warranted therapies. To prepare future treatment trials in RFC1 we here propose to chart the prospective feature evolution and longitudinal natural history of RFC1 disease.

Recent work by our study group leveraging a large international multicenter cohort of 70 RFC1 patients has demonstrated that RFC1 disease is an intrinsically multisystemic disease, involving several other features and systems beyond the classical cerebellar, sensory and vestibular systems, including hyperkinetic and autonomic features. Moreover, first natural history data demonstrate that disease progression is highly variable, including non-linear and highly rapid disease progression trajectories (Traschütz et al, Neurology, 2021).

In this project, we propose to perform a well-standardized prospective global 2-year multicenter natural history study on RFC1, comprehensively capturing multiple outcomes across all key outcome measure domains required for future treatment trials:
(1) Leveraging our well-established web-based multi-center collaborative ARCA registry, with already 31 centers contributing, we will be systematically collecting clinical outcome measures comprising of SARA and, INAS, as well as a novel CRF specifically targeting further CANVAS-specific disease features. The ARCA registry uses the same front-end as the SPORTAX, SCA and HSP registries, thus facilitating rapid and easy access as well as user-friendly use for participating centers around the globe.
(2) Prospective longitudinal brain MRI will be performed according to harmonized protocols
(3) Digital outcome measures will be identified using APDM and Q-Motor sensor protocols and infrastructure, as already established by us for multisystemic ataxias in the course of our joint European PROPSAX consortium, thus enabling enrolment with harmonized assessment protocols all participating RFC1 sites.
(4) To explore robust biomarkers outcomes, cross-center harmonized biosampling will be performed using the established PROSPAX biobanking protocol, as also already enrolled for the PROPSAX consortium at several European and Canadian sites, thus again maximizing synergies with existing cross-center protocols.

The existing infrastructure elements on these levels will thus facilitate the rapid implementation of this multimodal natural history study. Vice versa, this RFC1 natural history study will expand current AGI infrastructure by novel sustainable modules, including CRFs for its registries (e.g. CADN, CCAS) as well as infrastructure for harmonized collection and sharing of brain MRI, speech recordings and digital vestibulo-oculomotor data.

We are looking for:
Partners worldwide dedicated to contributing RFC1 patients to this natural history study, with commitment to longitudinally assess at least a limited number patients in all core modules before additional funding is acquired.

We can help you out with:
Providing ready-to-use harmonized protocols for clinical and digital-motor assessments as well as biobanking, and templates for patient consent and IRB application.

Cohorts used RFC1
Funding available? Key infrastructure established, additional funding to be sought as study and pilot data emerges
Trial readiness category 2: setting the stage for trial readiness (general cohorts, outcome measures or treatment approach identification)

Contact persons:
Selina Reich
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany

Matthis Synofzik
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany

Andreas Traschütz
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany

Further project partners:
(1) Partners in PROSPAX and PREPARE consortia
Nazli Basak
Koç University, Istanbul, Turkey
Bernard Brais
McGill University, Montreal, Canada
Alexandra Durr
ICM Institute, Paris, France
Helene Puccio
University of Lyon, Lyon, France
Filippo M. Santorelli
University of Pisa, Pisa, Italy
Bart van de Warrenburg
Radboud university medical center, Nijmegen, the Netherlands
Stephan Zuchner
University of Miami, Miami, USA

(2) Additional partners of the RFC1 natural history study group
Mathieu Anheim
University of Strasbourg, Strasbourg, France
Norbert Brüggemann
University of Lübeck, Lübeck, Germany
Alessandro Filla
Federico II University Naples, Naples, Italy
Jose Gazulla
Hospital Universitario Miguel Servet, Zaragoza, Spain
Ian Harding
University of Melbourne, Melbourne, Australia
Annette M. Hartmann
University of Halle, Halle, Germany
Jon Infante
University of Cantabria, Santander, Spain
Thomas Klockgether
University of Bonn, Bonn, Germany
Martin Paucar
Karolinska University Hospital, Stockholm, Sweden
José Luiz Pedroso
Federal University of São Paolo, São Paulo, Brazil
Richard Roxburgh
University of Auckland, Auckland, New Zealand
Michael Strupp
Ludwig Maximilian University of Munich, Munich, Germany
David Szmulewicz
University of Melbourne, Melbourne, Australia
Alexander Tarnutzer
University Hospital Zürich, Zürich, Switzerland
Dagmar Timmann-Braun
University of Essen, Essen, Germany
Adam Vogel
University of Melbourne, Melbourne, Australia