Projets de Recherche

Dans le cadre de sa mission de développer un traitement pour l’ARSACS, la Fondation est heureuse d’annoncer les projets de recherche qui seront financés en 2020-2021. La Fondation tient à remercier tous les candidats pour leur intérêt et pour la qualité de leurs soumissions. Il est à noter que la description n’est disponible qu’en version anglaise.

Parce que la recherche guérit!

“Discovery of new targets for therapeutic interventions in ARSACS disease” – Dr Nevan Krogan

Vidéo décrivant le projet du Dr Nevan Krogan “Discovery of new targets for therapeutic interventions in ARSACS disease”

“The development of novel treatments, through the discovery of new drugs or the repurposing of FDA-approved drugs and INDs, requires a detailed understanding of the biology of disorders. Protein complexes and networks work together to ensure healthy cell physiology and are altered in disease. Uncovering how disease mutations alter protein networks opens the door for novel target identification and allows the investigation of how drugs can restore a healthy state. To rapidly identify new protein targets for therapeutic interventions for ARSACS disease, we will apply unbiased mass spectrometry-based proteomics and innovative computational approaches to globally uncover the cellular signaling pathways and kinases affected by deletion of the SACS gene. We will use this information to identify drugs acting on the protein targets in these pathways and test them in cell culture assays. While we plan to identify both novel as well as existing drugs for therapeutic benefit, we will prioritize FDA-approved compounds as well as new investigational drugs (INDs). This “drug repurposing” strategy provides an expedited path from discovery to translational impact for this debilitating and poorly-studied condition. Once promising drug candidates have been identified, subsequent studies can be designed to test candidates in animal models and human clinical trials”.

Financement: 151,520$ USD

Le projet de recherche est financé en partenariat avec la Fondation de l’UCSF, Laboratoire Krogan en l’honneur d’Allison Trainor.

Durée: un an


Dr. Nevan Krogan, Cellular Molecular Pharmacology School of Medicine, University of California San Francisco
1700 4th Street,San Francisco, California, CA 94158

Tel: 415 476 2980


“Towards the Structural Determination of Sacsin”- Dr Walid Houry

The Houry group is interested in characterizing the structure and function of Sacsin. To this end, the group has generated a cell line expressing endogenously tagged SACS gene. This will be used as a tool to study the localization of the protein under different growth and stress conditions as well as for other cell biological studies. Furthermore, the cell line will allow for the purification of the tagged protein and its subsequent biochemical and structural characterization.

Grant: $74,000

Duration : 2nd year of the project


Dr. Walid A. Houry, Department of Biochemistry Faculty of Medicine, University of Toronto
661 University Avenue,Mars Centre, West Tower, Room 1612, Toronto, ON Canada M5G 1M1

Tel: 416 946 7141; Fax: 416 978 8548


“Therapeutic Approaches for ARSACS”- Dr. Benoit Gentil

ARSACS is characterised by the lack of sacsin expression and the formation of intermediate filaments bundles in neurons and fibroblasts derived from skin biopsies. Our strategy over the last years has been aimed at developing a replacement therapy, by peptide and/or gene vectors and, because of the chaperone function of sacsin, to investigate the potential of alternative therapies already in development in our laboratory to promote protein chaperoning. We have defined minimal domains necessary for the replacement therapy and identified that HDAC inhibitors have a strong therapeutic potential. For the next year, we will pursue our efforts.

AIM 1. Development of peptide and gene therapies. We have generated a AAV9 carrying a combination of sacsin domains and generated peptides derived from sacsin domains. We will test the efficacy of this vector in resorbing intermediate filament bundles in neurons.

AIM 2. Assessment of therapeutic potential of brain permeant HDAC inhibitors for ARSACS. We will examine the role of different HDACs inhibitors in resorbing intermediate filaments bundles in culture.

Grant: $100,000


Dr. Benoit Gentil, Department of Kinesiology and Physical Education, McGill University
475 Pine Avenue West, room 210, Montreal, Quebec  H3A 2B4

Tel: 514-398-4184 ext 00102

“Targeting mitochondrial fission in the Sacs KO mouse model of ARSACS”- Dr. Stefan Strack

ARSACS is a devastating neurological disorder caused by the loss of the Sacsin protein. Sacsin knockout (KO) mice recapitulate the cardinal symptoms of ARSACS, and research with these mice could therefore both help understand and ultimately cure the disorder. Mitochondrial dysfunction due to defective mitochondrial fission has been proposed as a primary cause of neurodegeneration in ARSACS. Other evidence suggests that mitochondrial dysfunction may be secondary to cytoskeletal abnormalities.

Our work aims to settle this controversy by crossing Sacs KO mice with mice that lack either positive (PP2A/Bbeta2) or negative (PKA/AKAP1) regulators of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Published and unpublished evidence suggests that both genetic manipulations are likely to influence the progression of the disorder, which we will monitor both behaviorally and with ex vivo imaging techniques. Outcomes from this project will illuminate the role of altered mitochondrial dynamics in ARSACS pathogenesis and point to novel avenues for treatment.

Grant : $71,750 USD


Dr. Stefan Strack

Dr. Stefan Strack

Dr.Stefan Strack, Professor of Pharmacology University of Iowa Carver College of Medicine
2-452 BSB, 51 Newton Rd. Iowa City, IA 52242
Tel:(office/lab): (319)384-44[39/47]; Fax: (319) 335-8930

“Elucidating mechanisms underlying motor coordination rescue in a mouse model of ARSACS” -Dr. Alanna Watt, & Dr. Anne McKinney

Aim 1 Identifying druggable Targets for potential ARSACS treatment
We have recently identified that the endosomal Na+/H+ exchanger NHE6, which is involved in regulating pH, is downregulated in anterior Purkinje cells of Sacs/ mice. Interestingly, these are the Purkinje cells that are more susceptible to cell death in ARSACS. Could the loss of NHE6 contribute to Purkinje cell death? Proper pH is essential for endosomal function, and changes result in erroneous trafficking of cargo. NHE6 results in overacidifcation of recycling endosomes which prevents the trafficking of cargo to the appropriate sites in neurons resulting in their dysfunction. For example, endosomal trafficking is important for controlled transport of glutamate receptors that mediate synaptic transmission, which we previously reported was altered in in Sacs-/- mice. We will now restore endosome acidification and cargo mistrafficking in Sacs/ to see if this prevents synaptic deficits and cell loss. Additionally, we have evidence suggesting Mito-Q as a novel therapy to improve mitochondrial function, prevent cell loss, and improve cerebellar-related motor coordination in Sacs/ mice.

Aim 2 Characterize pathophysiology for future druggable target development
We continue to pursue the identification of novel druggable targets by understanding the pathophysiological alterations that give rise to dysfunction in Sacs/ mice. To this end, we are exploring whether changes in Purkinje cell firing, and/or their innervation of downstream targets in the DCN, contribute to Purkinje cell loss and motor coordination deficits in in Sacs/ mice.

Grant: $125,000
Second year of a 2 year project
Dr. Alanna Watt

Dr. Alanna Watt,Department of Biology McGill University Bellini Life Sciences Bldg.
3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1 Office: Rm. 265 | Lab: Rm. 257
Tel: (514)-398-2806; Fax: (514)-398-5069; Email:

Dr. Anne McKinney

Dr. Anne McKinney, Department of Pharmacology and Therapeutics, McGill University Bellini Life Sciences Bldg
3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1
Tel: (514)-398-5685; Fax: (514)-398-2045; Email:

“Understanding the role of Metals in ARSACS” – Dr. Graham George

Seeking a link between ARSACS and essential metals

ARSACS is one of approximately 40 known human diseases that involve protein misfolding. Apart from ARSACS all of these diseases have been linked to dysregulation of essential transition metal ions, but this has never been investigated for ARSACS. Our research will employ state-of-the-art synchrotron X-ray methods to establish whether or not metal dysregulation is involved in ARSACS. We hypothesize that essential transition metals are perturbed in ARSACS, and that this perturbation is relevant to the development of the disease.

Grant : $65,000
This research project is funded jointly with the Richardson Research Fund who contributed $50,000 in addition to the contribution from the Foundation.


Dr. Graham George,College of Arts & Sciences,University of Saskatchewan
9 Campus Drive
Saskatoon, SK S7N 5A5>

“Characterization of Tau Hyperphosphorylation in ARSACS”- Dr. Anthony Hickey et Dr. Justin Wolter

The goal is to explore the misregulation of Tau in ARSACS, and evaluate the efficacy of modulating levels of Tau and associated kinases in the ARSACS mouse model.

Grant : $139,962


Dr. Anthony Hickey, Director of UNC Catalyst for Rare Diseases, University of North Carolina

120 Mason Farm Road CB# 7356, Chapel Hill NC 27599
Tel: (919) 962-9819

Dr.Justin Wolter

120 Mason Farm Road CB# 7356, Chapel Hill NC 27599
Tel: (919) 962-9819

“Creating an Open Science Repository of ARSACS hiPSCs”- Dr. Nicolas Dupré

Studying ARSACS pathophysiology and screening for therapeutics using sick human neural cells instead animal cells or cell lines is highly desirable but challenging because of the difficulty to access these cells without harming patients. It is possible to reprogram patients’ cells into human induced pluripotent stem cells (hiPSCs) and then to redifferentiate hiPSC into neural cells. This strategy is being exploited more and more to study an increasing number of neurological disorders. We propose to create an open and accessible repository of ARSACS hiPSCs reprogrammed with the Sendai virus method in order to significantly increase the availability of research resources in the best interest of patients. Peripheral blood mononuclear cells (PBMC) will be isolated from blood samples of participants and reprogrammed at the iPSC Québec platform (CHU de Québec-Université Laval). Then, cells will be stored in the C-BIG repository (McGill) in order to facilitate their distribution worldwide to all ARSACS researchers. Through this project, resources made available to the ARSACS research community will be increased.

Grant: $ 72,000


Dr. Nicolas Dupré
CHU de Québec
1401, 18e Rue
Département des sciences neurologiques
Québec, Québec
Canada G1J 1Z4
+1 418-649-0252, poste 63177

Is ARSACS a Tauopathy?- Dr. Paul Chapple

Currently we are looking carefully at sacsin’s interaction with cytoskeletal proteins and defining the molecular mechanisms by which sacsin’s loss disrupts cytoskeletal function. This includes research examining a link between cytoskeletal disruption, caused by loss of sacsin, and impaired formation of structures called focal adhesions that are important for cell movement. We are also looking at links between ARSACS and other neuronal diseases where cytoskeletal dysfunction is a feature, including Alzheimer’s disease. One of the key challenges that we wish to solve is understanding how all of the different problems identified in cells that do not have sacsin are integrated together. If we fully understand the ‘hierarch of events’ in the molecular pathology of cells that lack sacsin it will potentially facilitate the development of treatments for ARSACS.

Duration: 2nd year of a 3 year funded project

Grant: 32,827 pounds


Dr. Paul Chapple

Dr.Paul Chapple, Professor of Molecular Cell Biology
Centre for Endocrinology Barts and The London, Queen Mary’s School of Medicine and Dentistry
1st Floor North ,John Vane Science Building,Charterhouse Square
London, EC1M 6BQ
T: +44 (0) 20 7882 6242