The recent media blitz about a leukemia drug named Nilotinib as a potential treatment for Parkinson’s disease resulted in thousands of patients and family members phoning their doctors and our 1-800-4PD-INFO Helpline requesting access to this drug. The National Parkinson Foundation quickly responded with a public statement recommending that patients not pursue this therapy unless under a clinical trial. There were serious concerns in the size and methodology of this initial report which was recently presented at the Society for Neuroscience meeting. Patients and families should be aware that the results have yet to be published in a peer-reviewed paper. Please see the statement NPF Recommends Further Study but Not Clinical Use of this Investigational Drug. In this month’s What’s Hot in PD? column I will address the question as to what actually led scientists to believe a cancer drug could treat Parkinson’s disease?
Approximately 10% of Parkinson’s disease cases have been associated with gene defects. These changes in the DNA have allowed researchers to hone in on the mechanisms that may be responsible for this devastating disease. Scientists around the world have become adept at preparing animal models of Parkinson’s disease by using the observed changes in the DNA occurring in some human cases. Ted and Valina Dawson, a husband and wife team located at the National Parkinson Foundation Center of Excellence at Johns Hopkins University recently published an important paper on how the most common genetic subtype of Parkinson’s disease (LRRK2) leads to degeneration and to cell death.
Mutations in the DNA of Parkinson’s disease patients located in the leucine-rich repeat kinase 2 region (LRRK2) represent the most common genetic cause of Parkinson's disease. Because LRRK2 is the most common gene defect responsible for Parkinson’s disease, it has been a focus of many laboratories. So what does LRRK2 do? One of the jobs of LRRK2 in the brain seems to be to tag proteins. When proteins are tagged, this signals the brain to change its cell manufacturing process. However, when bad LRRK2 tags proteins, it results in over-manufacturing. An excess of proteins can lead to the death of brain cells. Bad LRRK2 performs its tagging function by attaching phosphate groups. Bad LRRK2 leads to increases in proteins through its action on a part of the cell called ribosomal s15. The Dawson duo demonstrated that by removing the phosphate group that tags s15 actually prevented degeneration. Further, by administering a low dose of anisomycin, which blocks protein production, the Dawson strategy also rescued flies with LRRK2 mutations.
Though these findings are exciting, we should remember that they have yet to be translated into humans. The Dawsons have suggested that one way to treat LRRK2 Parkinson’s disease would be to simply block phosphorylation of the s15 ribosomal protein. This idea may be formulated into a strategy for a future human clinical drug trial. Further, if there is a clinical trial, we will need a way to measure success and to monitor s15 phosphorylation. Phosphorylation could possibly be a blood or other biomarker of bad LRRK2 activity. The Dawsons have also for many years been investigating a class of drugs called the C-Abl tyrosine kinase inhibitors because of findings in another genetic form of Parkinson’s disease called PARKIN. The PARKIN protein is modified by c-Abl and this interaction could be the critical step leading to accumulation of toxic proteins in the brain. C-Abl inhibitors have been proposed as a way to block this protein buildup. The C-Abl pathway is where Nilotinib is thought to act, and this was proposed several years ago as a potential treatment for the protein buildups in Parkinson’s disease.
The Hopkins team carefully examined Nilotinib in 2013 (see http://www.ncbi.nlm.nih.gov/pubmed/24786396). “Our findings… suggest that Nilotinib and other brain penetrant c-Abl inhibitors could be used as disease modifying therapies in Parkinson’s disease. Consistent with this notion is the observation that Nilotinib reverses the loss of dopamine neurons and improves motor behavior in α-synuclein PD models. Based on the findings reported here and elsewhere, future studies are needed to identify the optimal dosing and administration to take advantage of the full neuroprotective potential of Nilotinib. Alternatively other c-Abl inhibitors with better pharmacokinetic properties and safety profiles may need to be identified to take advantage of inhibition of c-Abl as a disease modifying therapy for PD.”
Though the first dozen or so patients tested at the Georgetown site had positive effects, there were serious limitations to this study that patients and family members should be aware of:
- A very small number of patients (about a dozen); these trials usually require hundreds of patients to demonstrate an effect
- The design really only supported safety, but not effectiveness or efficacy
- The doses of the cancer drug administered were low, and if higher doses are required in future studies, toxicity may possibly limit this approach
- Many of the motor and cognitive outcomes improved in this small study and if a controlled study were performed it would be unlikely for all of these outcomes to improve
- Videotapes are not the most optimal way to assess outcome in a small study, and videotape methodology when not applied in a blinded and standardized fashion can lead to a large placebo effect or to an error in outcome interpretation
- There was no blinded comparison to a placebo or to another therapeutic approach
The good news, however, is that since 2013 Dawson and other investigators have been investigating potentially safer and more effective c-Abl inhibitor drug options. Patients and families should feel reassured that the scientific discoveries that led Parkinson’s scientists to repurpose Nilotinib, may also lead them to other and potentially better c-Abl strategies.
Okun, MS. 10 Breakthrough Therapies for Parkinson's Disease. Books4Patients. 2015.
You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.