Funding from The Parkinson Alliance helped to finance the following Parkinson’s research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.
Project Title: Environmental and Genetic Determinants of Progression in a Community-Based Cohort
Principal Investigator(s): Beate Ritz MD, PhD
Objective/Rationale: Parkinson’s Disease (PD) is a progressive disease known for its decline in motor- and non-motor functions and symptoms. PD progression is unpredictable over the course of the disease. Within a few years of diagnosis, some patients become wheelchair bound, cognitively impaired, severely depressed, and/or experience many other non-motor symptoms. In contrast other patients are spared major motor and non-motor disabilities despite having the disease for several years. There is a notable knowledge gap regarding the genetic and environmental factors that contribute to or modify the progression of PD. We aim to address this critical need by exploring the contributions of environmental toxins, genetic and epigenetic factors, and gene-environment interactions to PD’s complex progression phenotype.
Project Description/Methods/Design: This proposal builds upon our rich existing resources and expanding our data on PD patients followed longitudinally in the largest community-based cohort. Since 2000, we have been conducting the Parkinson Environment-Gene (PEG) study in rural central California with the aim to characterize contributions of pesticides and genes on the onset of incident idiopathic PD. We followed 250 patients diagnosed 1998-2006 longitudinally until 2012. All patients were assessed for depression (GDS, SCID), cognitive decline (MMSE), non-motor symptoms (such as sleep, autonomic dysfunctions etc.), lifestyle, behavioral, and medical factors and provided biological samples at baseline. While 235 were re-examined for motor and non-motor function (mUPDRS), 185 were seen twice during follow-up. Follow-up exams were conducted on average 3 and 5 years after the baseline PEG exam. We later enrolled another large group of PD subjects (PEG2) and have been following this 2nd cohort longitudinally as with the 1st PEG cohort. Approximately 900 PD subjects and 800 controls have enrolled in both cohorts.
We propose here to continue to collect measures of motor and non-motor progression on PEG2 subjects as well as biological samples. We will also determine if certain environmental (e.g. pesticides, medication, occupations etc), genetic polymorphisms (genetic variations), or epigenetic markers (environmental changes to genes that can be passed on) determine the rate of disease progression. Importantly, we will continue to share these resources (including the biologic samples) with other investigators around the world to help determine why some people progress faster than others.
Relevance to Treatment of Parkinson’s Disease: There are still no treatments that slow or stop the progression of PD despite several attempts. One reason for this is that we still do not know what determines the rate of progression in PD. Information from our studies will also be important in running a clinical trial on progression since it will help decrease the variability in the study population.
Expected Outcome: We anticipate that there will be several environmental and genetic factors that determine the rate of progression. These likely will include certain pesticides and genetic factors that alter alpha-synuclein metabolism.
Project Title: Phase IIa Safety and Tolerability Trial of Nilotinib in People with Parkinson’s Disease
Principal Investigator(s): Tanya Simuni, MD, Chief of Movement Disorders at Northwestern University Feinberg School of Medicine
Study Rationale: Previous research has shown higher levels of the c-Abl protein are activated in the brains of people with Parkinson’s disease (PD), and studies have linked c-Abl to pathways associated with the disease. Impeding the activity of this protein could potentially slow or stop the progression of PD, making it an emerging therapeutic target. While much work remains to understand the role of this protein in Parkinson’s, it showed early promise as a potential therapeutic target. A small open-label Phase I clinical trial evaluated the safety and tolerability of nilotinib, a c-Abl inhibitor, in people with Parkinson’s and preliminary data showed potential benefit.
Hypothesis: The Phase IIa trial aims to expand on preliminary safety findings and assess potential side effects to better understand the implications of nilotinib’s long-term use in Parkinson’s. The study also will further explore nilotinib’s potential to treat symptoms or to slow or stop disease progression.
Study Design: In The Michael J. Fox Foundation’s multicenter, randomized, double-blind, placebo-controlled Phase IIa trial, 75 people with moderate to advanced PD will be randomized to receive 150 mg of nilotinib, 300 mg of nilotinib or placebo daily for six months. Neither patients nor clinicians will know what therapy each person receives until the end of the trial. After six months, all treatments will be stopped and patients will be monitored for another 10 weeks. Results will be analyzed to determine if the drug is safe and tolerable, and which of the drug doses appears to be the maximum tolerated.
If outcomes provide conclusive safety data, a second funded trial will test the highest tolerated dose of nilotinib vs. placebo, again for safety and tolerability, in 60 people with early-stage Parkinson’s. Neither patients nor investigators will be aware of which treatment is being administered. After 12 months of daily dosing, therapy will be stopped and participants will be monitored for an additional 10 weeks.
Study leadership is working to secure in-kind donation of drug and placebo for use in the trial.
Impact on Diagnosis/Treatment of Parkinson’s Disease: The study aims to help researchers determine if nilotinib is safe for use in Parkinson’s disease. The study will also explore nilotinib’s potential to treat symptoms, or to slow or stop disease progression (something no current PD treatment has been proven to do).
Next Steps for Development: Recruitment will begin at clinical sites across the United States in September 2017.
Trial Phase: Phase IIa
September 2018 Project Update:
The study is being conducted at 25 Parkinson Study Group (PSG) sites in the US. The first participant was recruited in November 2017 and as of July 2018 half of the participants have been randomized into one of the treatment or placebo arms. Recruitment is expected to be completed in late fall 2018 after which participants will be followed through spring/summer 2019. More details about the trial can be found at www.clinicaltrials.gov (NCT03205488).