Trojan horse treatment for neurodegenerative disease

Dr. Dale Martin named a Future Leader in Canadian Brain Research

By Vanessa Parks
Internal Communications and Engagement Specialist

When asked about his research, Dr. Dale Martin has a simple answer. “We study why cells in the brain die in the hopes of developing therapeutics for neurodegenerative diseases,” he explains. On the other side of his office wall, his lab hums like something big is in the works. And it is.

Martin is a recipient of Brain Canada’s 2023 Future Leaders in Canadian Brain Research program, which supports emerging brain researchers working to develop cures for anything from depression to Alzheimer’s disease to brain injury.

Martin’s research explores genetic mutations that lead to neurodegenerative diseases. An emerging therapy for these diseases includes antisense oligonucleotides (ASOs), small molecules that can target genetic changes to prevent mutant proteins from forming, thereby delaying the progression of diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. ASOs are also showing great potential in treating Huntington’s disease.

To get ASOs past the blood-brain barrier, standard treatments involve injections directly into the spinal cord. Martin’s team has come up with a less invasive treatment solution. They have developed small carriers, called nanoparticles, that use proteins expressed in the liver to carry ASOs across the blood-brain barrier. These nanoparticles can be injected into the bloodstream.

“What we’ve done is hijack high-density lipoprotein (HDL), a cholesterol transporter,” Martin explains. “This protein needs to get to the brain, so we’ve modified it to carry ASOs, sort of like a trojan horse.”

With the funding from this Brain Canada grant, Martin and his team will focus specifically on a rare cluster of diseases called multisystem proteinopathy (MSP), which affect the brain as well as the bone and muscle. MSP is caused by mutations in the Valosin-containing protein (VCP) gene. Patients with this mutation, even members of the same family, can develop disease in any combination of these systems, while also developing ALS.

“I’m excited to be able to do more research directly into VCP disease because it is so rare and not a lot of research has been done in this area,” Martin says. “I’m happy to use this platform to help VCP disease patients and do a deeper dive into this space and how it relates to ALS. Through the Cure VCP Disease foundation, I’ve had the opportunity to meet multiple MSP patients and listen to their stories, which has inspired me and my lab to try to find new treatments for MSP. We are grateful for their co-operation and support for this project, which includes patients’ genome sequences.”

In addition to being rare, diseases caused by mutations in the VCP gene are difficult to treat. Whereas Huntington’s disease is caused by one mutation in a single gene, MSP is caused by more than 50 different mutations in one gene. Since each mutation would require a specific ASO, multiple ASOs are required to treat MSP. Martin’s team will look for commonalities among patients with VCP disease to see if they can identify one shared genetic target for all mutations.

The 2023 Future Leaders in Canadian Brain Research grant will allow Martin’s team to optimize their nanoparticles for the treatment of MSP. But this research will have a broader impact on the health of people living with other neurodegenerative diseases. Mutations in the VCP gene are also associated with Parkinsonism, hereditary spastic paraplegia (HSP), ataxia and ALS, among others.

“The nanoparticles we’re working with deliver to the brain, but they will deliver to the periphery as well, where they may have an additive effect in protection in ALS and MSP,” says Martin.

The Future Leaders in Canadian Brain Research program is made possible by the Canada Brain Research Fund, an innovative arrangement with the Government of Canada, through Health Canada and Brain Canada. The program was established by an anchor gift from the Azrieli Foundation and is supported by the Alvin Segal Family Foundation, The Arrell Family Foundation, the Hewitt Foundation, ALS Society of Canada, The Erika Legacy Foundation, the Lotte & John Hecht Memorial Foundation, the Barry and Laurie Green Family Charitable Trust, Women’s Brain Health Initiative (WBHI), and the Canadian Institutes of Health Research (CIHR-IRSC). 

Working with organizations like Brain Canada strengthens the ability of researchers to translate the work they do in the lab to real-world outcomes. This grant will support Martin and his team as they develop treatment options for a variety of neurodegenerative disorders, directly impacting Canadians living with these diseases.