Amsterdam, NL, July 12, 2016 – Parkinson’s ailment (PD) is the second most common neurodegenerative disorder that sets off a range of motor and non-motor symptoms. Throughout the road of the disease, dopamine (DA)-making neurons are lost and bundles of proteins known as Lewy bodies (LBs) form in the brain. A study reported in the Journal of Parkinson’s Disease offered molecular evidence that the FDA-approved leukemia drug nilotinib might restore brain dopamine and reduce toxic proteins associated along with LB formation in PD and dementia patients.
Researchers from Georgetown University Medical Focus conducted a small phase 1 study that included only 12 patients, primarily intended to evaluate whether patients could tolerate the drug. The outcomes showed unanticipated improvements in clinical outcomes and motor function.
“This is the very first study to handle subjects along with advanced PD along with a tyrosine kinase inhibitor,” explained lead investigator Charbel Moussa, MD, PhD, of the Department of Neurology, National Parkinson’s Foundation Focus for Excellence, Georgetown University Medical Focus (GUMC), Washington DC. “This study suggests that reduced doses of nilotinib appear to be relatively safe in a small cohort of participants along with advanced PD or dementia along with Lewy bodies (DLB), and despite the fact that the data are supportive of extra trials, caution ought to be used in any type of future studies. The data provide a clear signal to relocate forward along with much more definitive trials to find out an proper therapeutic dose and evaluate nilotinib effects in larger, randomized, double-blinded, placebo-controlled trials.”
Autophagy, a “housecleaning” process that removes various entities from inside cells, might be impaired in PD and DLB patients. Nilotinib is an Abelson tyrosine kinase inhibitor (Abl-TKI) that sets off autophagy to destroy cancer cells. The researchers had Located previously that this drug could penetrate the blood brain barrier and degrade the healthy protein bundles, which are primarily composed of α-synuclein. Based on this observation, they conducted a small proof-of-concept, non-placebo-controlled clinical trial.
Twelve patients along with late-stage PD or DLB randomized in to two teams were offered either 150 mg or 300 mg of nilotinib everyday for 6 months, significantly reduced compared to the 600-800 mg doses used in leukemia treatment. Careful safety monitoring included bodily and neurological exams, EKGs, and extensive blood chemistry testing. Blood and cerebrospinal fluid (CSF) were collected at the start of the study and again after 8 and 24 weeks. Nilotinib uptake was measured at various intervals after dosing, and a number of biomarkers associated along with PD and neurodegeneration were assessed.
“Patients gradually improved in motor and cognitive functions as long as they were on the drug — despite the decreased usage of dopamine substitute therapies in those participants along with Parkinson’s and dementia along with Lewy bodies,” specified the study’s lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Regimen and director of the Movement Disorders Regimen at MedStar Georgetown University Hospital.
In addition, motor symptoms were monitored using the Unified Parkinson ailment Rating Scale (UPDRS). The researchers observed improvements in every one of participants at 24 weeks, along with the effects reversing by the 36-week follow up visits, after treatment had concluded.
Among the biomarker findings were that:
- The degree of the dopamine metabolite homovanillic acid — an indicator that dopamine is being created — progressively doubled, even along with the loss of most dopamine neurons. Most study participants were able to protect against using, or reduce their usage of, dopamine substitute therapies;
- The degree of the Parkinson’s related oxidative tension marker DJ-1 — an indicator that dopamine-making neurons are dying — was reasonable much more compared to 50 percent after nilotinib treatment; and
- The levels of cell death markers (NSE, S100B and tau) were significantly reasonable in CSF suggesting reasonable neuronal cell death.
“Our chance is to clarify the incentives of nilotinib to patients in a a lot larger and well controlled study. This was a quite promising start,” Dr. Moussa said. “If these data hold out in further studies, nilotinib would certainly be the crucial treatment for Parkinsonism due to the fact that the discovery of Levodopa almost 50 years ago.”
He added, “Additionally, if we can easily validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the very first treatments for dementia along with Lewy bodies, which has actually no cure, and possibly others dementias.”
In an accompanying commentary, Richard K Wyse, MD, The Cure Parkinson’s Trust, London, UK, Patrik Brundin, MD, PhD, Focus for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA, and Todd B Sherer, PhD, Michael J Fox Foundation for Parkinson’s Research, Brand-new York, Brand-new York, USA, put these findings in to perspective and treat several of the limitations of this small yet innovative study. “The most recent paper by Pagan et al. substantiates a Brand-new direction, addressing a molecular pathway not previously targeted in a clinical trial in this context, for potential ailment change in PD and DLB. However, this study is simply a very first step and a significant concerted initiative is required to find out whether there is still chance that can easily suit the hype for nilotinib in alpha-synucleinopathies.”
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