Unblocking barriers to gene therapy

Non-invasive, endogenous neuronal regeneration via focused ultrasound and microbubble-mediated gene therapy in a Parkinson’s disease model

Delivering a new drug or agent that carries gene therapy directly to the areas of the brain affected by Parkinson’s is challenging.

It’s made more difficult by the blood-brain barrier: a physical border designed to block harmful molecules from entering the brain.

At Toronto’s Sunnybrook Research Institute, neuroscientist Dallan McMahon, a postdoctoral fellow, is devising ways to open the blood-brain barrier temporarily, long enough to enable targeted delivery of a gene therapy he hopes will help people with Parkinson’s.

“Blood vessels in the brain are specifically equipped to prevent a huge variety of molecules from inadvertently entering the brain,” McMahon explains.

McMahon, who is working with mouse models, is using microbubbles and ultrasound equipment to temporarily open gaps between the cells that line blood vessels in the brain.

By injecting microbubbles into the body and then focusing the soundwaves from an ultrasound on the brain, McMahon can cause the microbubbles to vibrate and create gaps between the blood vessel cells.

Those gaps – which can last from minutes to hours – will create enough space so a gene therapy agent injected into the body can travel through the bloodstream and enter areas of the brain affected by Parkinson’s.

The gene therapy agent consists of a modified, harmless virus that delivers instructions for a protein involved in brain development.

By sending this gene therapy agent directly into the areas of the brain where dopamine-producing brain cells are dying, McMahon hopes to trigger a process to create new dopamine-generating cells.

This approach should transform a different set of cells, called astrocytes, into dopamine cells, replacing the ones lost to Parkinson’s disease.

McMahon believes he is embarking on a promising new avenue.

“This is a combination of several fields of research, hopefully culminating in an effective treatment strategy,” says McMahon.

“If everything worked out perfectly and this was an efficient transformation of astrocytes to neurons, the hope would be a reversal of Parkinson’s deficits.”

For McMahon, working on Parkinson’s was a matter of recognizing a need and using his skills in ultrasound techniques and drug delivery to meet it.

Growing up on a farm in a hamlet north of Guelph, Ontario, he spent his early years observing, playing, and building structures in the woods – all good assets for his later research career, he says.

Although he knows his work may take years, McMahon believes it will pay off.

“The long-term benefits are the reason for making this kind of investment,” he says.

How your support made this research project possible

"This grant will allow me to focus my time on Parkinson's research, something that wouldn't otherwise happen," McMahon says.

"The potential for this research to eventually lead to a therapeutic treatment strategy is fairly high."

Even if McMahon's gene therapy approach cannot convert the brain's support cells (astrocytes) to dopamine-producing neurons, his work will lead to new knowledge around effective ways to deliver gene therapies to the brain, he says.