PHILIPPE GROS

Exploitation of a new pharmacological target for the development and validation of new anti-inflammatory drugs

Challenge: Neuroinflammation (NI) is involved in a diverse array of degenerative conditions, ranging from multiple sclerosis (MS) to Parkinson’s and Alzheimer’s disease. Although treatment options are available for MS their effectiveness is not uniform and long-term use has significant side effects. NI-based disorders remain an area of high unmet medical need and new approaches and targets are required to find disease-modifying therapies for patients.

Solution: In previous studies, the team discovered that inactivation of the ubiquitin-specific protease USP15 protects mice against lethal NI in microbial and autoimmune experimental models. The current project aims to develop and validate specific inhibitors of USP15 in view of managing and treating NI. To achieve these objectives, USP15 inhibitors of therapeutic value will be developed based on recently identified hits. Medicinal chemistry will be used to improve their potency, selectivity, and efficacy in blunting NI in vitro and in vivo, and preclinical studies will be conducted on selected lead(s). Furthermore, the function of USP15 will be investigated in different immune cell populations and brain cells where the protein is expressed, and cell-specific biochemical pathways where it acts will also be identified. Finally, different mouse models of inflammation will be used to map out therapeutic applications of USP15 modulators in neurological and neurodegenerative diseases.

Expected Achievements/Impact: The project will expand the therapeutic field for USP15 and map out USP15 pathways and associated partners in immune cells. This will lead to a better understanding of the functional role of USP15 in the brain and immune cells during NI and pursue the development and validation of small molecule USP15 inhibitors. At the completion of this project, the first known USP15 inhibitor(s) will be qualified and a lead candidate(s) ready to proceed into drug development identified. This research will provide the basis for the development of a first-in-class USP15-based therapy.

 

 

 

 

 

 

 

 

 

 

 

 

Principal Investigator:


Philippe Gros
McGill University

Co-investigator

Véronique Bougie
Corbin Therapeutics

Ongoing Project
$ 1,375,000 / 2 years
Supported by CQDM through:
• MEI
 
And by co-funding partners:
• Corbin Therapeutics
• Healthy Brains, Healthy Lives (HBHL)
• Brain Canada