What New Therapies for Parkinson’s Disease Are on the Horizon?
Alpha Synuclein Receives Renewed Attention
The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.
Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.
Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.
An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.
Exercise May Improve Outcomes
Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.
Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.
The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.
“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”
—Erik Greb
Suggested Reading
Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].
Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.
Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.
