For Joe Kelley and the CSRA Parkinson Support Group, their investment in the research of neuroscientist Bobby Thomas at Augusta University is paying off, not just in the millions of dollars in federal research money Thomas recently received, but in less tangible results.
“My initial reaction is good, there’s another chance. There’s another chance that this will be resolved,” said Kelley, a Parkinson’s disease patient for 15 years and vice president of the support group.
Thomas was recently awarded a $1.9 million, five-year grant from the National Institutes of Health to explore ways of stimulating a hotly pursued pathway for regulating genes involved in antioxidants, molecules that reduce free radicals that can cause the oxidative stress, leading to the damage that causes Parkinson’s. Most of the current treatments for Parkinson’s seek to control the symptoms of the disease, such as tremors and balance problems.
Thomas is pursuing a strategy that seeks to protect and preserve the neurons whose slow loss leads to the disease. His research has always focused on a particular pathway, abbreviated as Nrf2, that has received a lot of attention not only from Parkinson’s researchers, but from others for its role as a master regulator of antioxidant response element genes.
Last year, Thomas was pursuing research on a drug used in multiple sclerosis called dimethyl fumarate that appeared to activate the Nrf2 pathway. Unfortunately, Thomas said, he discovered that it did that by modifying another important protein that is abbreviated as Keap, which targets unwanted proteins and gets rid of them through a “garbage disposal” mechanism in the cell.
Without it, “there will be a lot of unwanted proteins in the cell, they will accumulate and eventually it will damage the cell,” he said. “You don’t want to alter that function of the cell.”
While the Nrf2 mechanism has generated a lot of excitement, not just for Parkinson’s but for other diseases, that is a common problem researchers run up against, Thomas said.
“It is very well-known that this pathway is promising from a therapeutic standpoint,” he said. “But the challenge has been how to activate it in a safe manner.”
Clinical trials in the U.S. currently trying to target the mechanism are looking at, oddly enough, broccoli sprout extract or the chemical component of broccoli sprouts that appears to be active, known as sulforaphane, in chronic kidney disease or rheumatoid arthritis. Another one being studied is curcumin, which is found in the spice turmeric. Those approaches might activate the pathway, but they will likely run into the same problem, Thomas said.
“The challenge in the field has been that all activators of Nrf2 modify Keap,” Thomas said. “As part of this project, we are utilizing an alternate approach.”
His research is now focused on a protein called Bach, which normally sits on those antioxidant response genes and suppresses their activity. Blocking the activity of Bach allows Nrf2 to activate those genes, Thomas said. He is working with a company called vTv Therapeutics that already has a Bach inhibitor drug they are trying to develop. Interestingly, in mice bred to lack the Nrf2 gene, the Bach pathway still appears to work in activating the antioxidant genes, Thomas said.
“Targeting Bach may be a much more potent pathway to activate this (antioxidant) pathway,” he said. Because the company already has the inhibitor under development, if Thomas’ preclinical work in animal models shows promise “then the company plans to run clinical trials on patients,” he said.
That outcome is just what the support group hoped when it gave Thomas $10,000 to do the foundation of the work that led to the grant, Kelley said.
“Several of our recipients do that here at Augusta University, use our grant for proof of principle and then give the proof of principle to NIH for larger grant applications,” Kelley said, “because we can’t fund them fully.”
Reach Tom Corwin at (706) 823-3213 or firstname.lastname@example.org.