The objective of the Accelerate Grants is to support research aimed at improving the commercial potential of a neuroscience-related technology and to position it for commercial development.
| HBHL Research Theme | Principal Investigator | Partner(s) | Project Title | Funding Received |
|---|---|---|---|---|
| 2 | Philippe Gros | Corbin Therapeutics | Commercialization of USP15 as a therapeutic target in Neuroinflammation and Parkinson’s Disease: Studies in USP15 defective Human Astrocytes and Human Microglia, and Development of potent and selective USP15 inhibitors |
Total: $454,000 HBHL: $200,000 |
| 4 | Salah El Mestikawy | Development of Donquine and analogs, first-in-class drug candidates to treat anorexia |
Total: $540,000 HBHL: $190,000 |
Funded Project Summaries
Commercialization of USP15 as a therapeutic target in Neuroinflammation and Parkinson’s Disease: Studies in USP15 defective Human Astrocytes and Human Microglia, and Development of potent and selective USP15 inhibitors
We aim to advance USP15 inhibition as a therapeutic avenue for NI in PD. Our proposal has 3 strategic aims. First, we will establish whether USP15 contributes to NI and neurodegeneration in human astrocytes and human microglia, and establish whether targeting these cells for USP15 inhibition is of therapeutic value in humans. We will create human pluripotent stem cells that express mutant USP15 variants introduced by knock-in, and will derive USP15-defective human astrocytes and microglial lines. We will characterize the effect of USP15 mutations on functional properties of astrocytes and microglia in vitro, including activation to pro-inflammatory phenotypes associated with NI in PD. Second, we will develop USP15 inhibitors of therapeutic value based on our recently developed hit series that show strong potency with good SAR, with selectivity for USP15, and promising activity in cell-based assays. We will use medicinal chemistry and structure-based approaches (X-ray crystallography) to improve their potency, selectivity and efficacy in blunting NI in vitro and in vivo. We propose to conduct preclinical studies of our best inhibitors, including pharmacokinetics, toxicology and efficacy in vivo.
HBHL Research Theme: 2
Principal Investigator: Philippe Gros
Funding Received: $454,000
Development of Donquine and analogs, first-in-class drug candidates to treat anorexia
Almost 1 million Canadians suffer from eating disorders such as anorexia nervosa. Currently, there is no specific treatment for anorexia nervosa. Excessive habits are at the heart of self-destructive behaviors observed in anorexia. We recently established that the neurotransmitter named acetylcholine is a pivotal regulator of anorexia-like behavior in mice. We also identified that donepezil (Aricept), a well-known acetylcholine esterase inhibitor, corrects these deficits. These findings represent a major breakthrough in the field. However, pro-cholinergic drugs (such as donepezil) have numerous peripheral side effects. We propose to develop derivates of donepezil with increased capacity to penetrate the brain. We used an in-silico docking strategy to identify a drug candidate, LMB1-01-002, that virtually showed 30-fold higher potency than marketed donepezil. At low doses, LMB1-01-002, restored normal eating behaviour in a relevant rodent model of anorexia. Low dose regimens will help reduce or eliminate deleterious side effects. This program will lead to first-in-class, specific pharmacological treatment for anorexia with high potential to expand to broader compulsive disorders such as OCD and addiction.
HBHL Research Theme: 4
Principal Investigator: Salah El Mestikawy
Funding Received: $540,000
