In a prior post, I told the story of how a genetic mutation provided insight that can help everyone with Parkinson's. The story of nilotinib is an exciting development leveraging that same model. As with isradipine, inosine, and other studies, this is a case where a fundamental understanding of biology informed the development of a drug we hope can make a difference.
Back in 1998, a group of Japanese researchers first connected the gene for a protein they named parkin with juvenile-onset Parkinson's disease. Parkin is one of the most important genes for Parkinson's, representing the most important recessive genetic cause of Parkinson's. Recessive genetic disorders (i.e., both parents must be carriers) are interesting to scientists because they are situations where people get a disease because a cellular process doesn't happen. Since DNA codes for proteins, and humans have two copies of each string of DNA -- one from each parent -- only when both copies of the code for a protein are damaged does the DNA not work at all. When that protein is important for a biological process to work, if the body can't synthesize it, that process won't happen.
Patients with parkin-related Parkinson's provide us with unique insight into the disease. With alpha synuclein, there are lots of ways it could be problematic. With parkin, we know we can look just at the cellular processes where the protein is necessary.
Parkin is a protein that attaches to things in cells to trigger the process of garbage collection -- cells contain tiny structures, lysosomes and proteosomes, that are involved in breaking up things in the cell that are not needed. Both lysosomes and proteosomes have been linked to Parkinson's disease. A scientist I've supported, Ted Fon, is studying parkin. His team has shown that parkin is linked to mitochondria -- the power plants in cells. Recent research has suggested that alpha synuclein converges with parkin at the mitochondria.
Since alpha synuclein is the most important protein in Parkinson's and parkin is second, this convergence probably points to something important.
As these connections are found, there is increasing enthusiasm for the idea that we could stop Parkinson's at the cellular level by addressing this "garbage collection" problem. A team led by a brilliant scientist at Johns Hopkins named Ted Dawson figured out that a cellular chemical called c-Abl, which is a tyrosine kinase (this simply means that it is involved in regulating protein activity) and is connected to a form of leukemia, was also active in the brain. Professor Dawson and his colleagues realized that c-Abl might be "turning off" parkin in the brain and that this was connected to Parkinson's. If we could block c-Abl from turning off parkin, then maybe we could reverse the build up of protein in cells that we think is important in Parkinson's disease at the cellular level.
Funded through NIH's Udall Centers program, the Dawson Lab started looking at whether c-Abl could be inhibited. Other labs also pursued this target, including animal tests of imatinib and nilotinib, two leukemia drugs -- the latter by a biologist at Georgetown, Charbel Moussa. The nilotinib results were promising and replicated at another lab. Moussa found that nilotinib reversed alpha synuclein accumulation in a mouse model of Parkinson's. The team at Dawson's lab also studied nilotinib, and recommended that a phase I trial be initiated.
Moussa, working with the director of the National Parkinson Foundation Center of Excellence at Georgetown University, a neurologist named Fernando Pagan, launched a clinical trial of nilotinib for Parkinson's. The results of that trial were presented at the Society for Neuroscience meeting in Chicago this month. The press focused on the symptomatic benefits, but most scientists will tell you that we can't tell the difference between the the drug effects and placebo effects in a trial like this. (The story of intravenous glutathione -- positive open label, negative randomized controlled trial -- is an example.) The best we can say about the phase I trial at Georgetown is that it could have contradicted the very promising animal studies, and it didn't: tests of patients' spinal fluid suggested that the benefit might be real. [Update: Ted Dawson told the Udall Center Directors meeting that he felt the dose in the Georgetown trial was too low, so it's not clear what we might see beyond placebo benefit. Update 2: Moussa says that the lower dose is effective because we don't need to inhibit c-Abl all the time, just for for a portion of the day, since these cellular processes can occur very quickly. The dose effective in cancer inhibits c-Abl around the clock.]
Further testing is clearly required. People often say this when they mean, "someone who is widely respected and/or gives out a lot of money has said something and I don't want to contradict them." In this case, however, I mean what I'm saying: we need more testing.
There is good reason to believe that it is fundamentally possible to slow or stop Parkinson's, and it is possible that if we did that, the brain would recover... somewhat. The discovery of c-Abl as a target was done through good science, with biology, hypothesis testing and replication and all the good stuff of serious science. It is possible but certainly not definite that c-Abl inhibition is the path to do this. However, remember that this is chemotherapy. Chemotherapy has a bad reputation for side-effects with good reason. There are other promising studies, too, and we need to trust the scientific process as much as we put our chips on one drug in the pipeline or another.
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