Michael J. Fox Foundation Awards $1 Million for Development of "Trojan Horse" Delivery Technology to Treat Parkinson’s Disease
ArmaGen’s novel approach would use molecular bio-engineering techniques to “trick” the brain into allowing large-molecule (e.g. protein-based) therapeutics across the blood-brain barrier in order to access targeted regions of the brain and address the neuronal loss that characterizes Parkinson’s disease. If successful, the work could yield a first-in-class drug that would increase the feasibility of treating PD with therapeutics including trophic factors — specialized, naturally occurring proteins that protect and nourish neurons — by allowing for delivery via non-invasive intravenous administration.
“At The Michael J. Fox Foundation, we believe that our capital has an obligation to fund high-risk, high-reward projects that, if successful, could significantly improve the lives of people with Parkinson’s,” said Katie Hood, CEO of MJFF. “A major element of our work is the identification and prioritization of approaches like ArmaGen’s — efforts that without our backing would likely stall for lack of resources.”
The blood-brain barrier surrounds the brain and functions to keep out pathogens and other harmful agents. While critical to human health, it presents one of the most daunting challenges for delivery of drugs used to treat PD and other central nervous system disorders. Some of the therapeutic approaches that currently show the most promise to yield transformative treatments for PD involve the use of so-called “large molecules” that are unable to penetrate the barrier. These approaches, which include trophic factors, currently require brain surgery, an inherently risky and invasive intervention, to access the brain regions affected in Parkinson’s. (In March 2008 the Foundation launched a $2-million initiative, Improving Delivery of Parkinson’s Disease Therapeutics to the Brain, solely designed to address PD drug delivery; funding is anticipated in October.)
Building on earlier work funded by MJFF under its Community Fast Track initiative, the ArmaGen team, led by principal investigator Ruben J. Boado, PhD, will work with the trophic factor GDNF. They will try to enable it to cross the blood-brain barrier by re-engineering it using Trojan horse technology. The end goal is to create a safe and effective treatment in which GDNF, fused to a genetically engineered antibody that is naturally capable of crossing the blood-brain barrier, can be injected intravenously into the blood. The antibody, “hiding” the GDNF inside itself — as the Trojan horse of Homer’s Iliad hid Greek soldiers, allowing them to enter Troy — would then ferry the attached GDNF across the blood-brain barrier, from the blood to the target site in brain.
“Trojan horse technology has intrigued Parkinson’s researchers for years because of its theoretical potential to overcome the drug delivery hurdle, one of the single most significant challenges facing the entire field,” said Gene Johnson, PhD, chief scientific advisor to MJFF. “It is fitting that The Michael J. Fox Foundation, which is searching urgently for treatments that will significantly modify Parkinson’s disease, should provide funding to vet the potential of this technology to yield new therapies that could transform patients’ lives.”
The researchers have three major goals: first, to successfully engineer the fused GDNF; second, to inject it into non-human primates and test its safety, its potential toxicity and its ability to penetrate the blood-brain barrier and permeate the targeted regions of the brain; third, to determine whether the treatment alleviates symptoms and pathology of PD in the animal model. To receive full funding, the team must demonstrate that it has achieved all three of these goals.
Assuming all milestones are met and the treatment proves safe and effective in animals, the researchers hope to initiate clinical testing in human patients within five to seven years.
A detailed lay abstract and researcher bios are available at www.michaeljfox.org.