Elevated axonal and myelin injury with aging: Mechanisms, prevention and prospective therapeutics for progressive multiple sclerosis
Principal Investigator: Dr. Wee Yong
Affiliation: University of Calgary
Amount Awarded: $420,140
Keywords: Repair, Neuroprotection, Progressive MS, Remyelination, Indapamide
- Age is a key factor associated with progression from relapsing to progressive forms of multiple sclerosis (MS).
- Destructive oxygen radicals are activated in MS and may play a role in age-dependent injury. How they are activated and cause injury is unknown.
- The research team will:
- Examine aging-enhanced injury in MS by targeting oxygen radicals
- Validate an antioxidant, indapamide, as a novel therapeutic that alleviates aging-enhanced injury
- Examine the combinational efficacy of both indapamide with a generic drug currently tested in progressive MS trials
Most individuals with MS begin with a relapsing-remitting course of the disease and then progress to secondary progressive MS (SPMS). Age is one factor that is crucial for the conversion from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS), however, why age is associated with progression and what can alleviate this age-dependent effect remains unknown. Preliminary experiments from Dr. Wee Yong’s laboratory have revealed that young mice (akin to a 20-year-old human) and aging animals (representing 50-year-old humans) with identical myelin-disrupting injury to the spinal cord caused larger lesion volume and more degeneration in the aging cohort. Greater injury in aged mice is hypothesized to be caused by a pathway that produces destructive oxygen radicals—a pathway also known to be activated in MS. This has led the Yong research team to test whether they can alleviate the aging-enhanced spinal cord injury by targeting this pathway. Moreover, the research team plans to validate the utility of indapamide—a generic medication used to treat hypertension and identified as an oxygen radical neutralizer (an anti-oxidant) in a previous screen for medications for progressive MS—as a potential medication to alleviate aging-enhanced neural injury. Finally, given the prospects of combination efficacy, the team will use the anti-oxidant indapamide together with another generic medication that is already being tested in a trial in primary progressive MS, named hydroxychloroquine. The ultimate goal of this project is to establish a novel therapeutic (indapamide, with and without hydroxychloroquine) for treatment of progressive MS.
Potential Impact: Establish an antioxidant as a novel therapeutic for the treatment of progressive MS.
Project Status: In progress