Abstract Details

Title Nilotinib alters microRNAs that regulate specific autophagy and ubiquitination genes in the CSF of individuals with Parkinson’s disease

Topic Movement Disorders

Presentation(s) S41 - Parkinson's Disease Interventions and Clinical Trials (2:36 PM-2:48 PM)

Poster/Presentation
Number 009

Objective We evaluated the effects of nilotinib on microRNAs (miRNAs) in the cerebrospinal fluid (CSF) of Parkinson’s disease patients.

Background MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that may potentially regulate gene expression at the –post transcriptional level. Our preclinical data demonstrated that the principal effects of nilotinib is clearance of misfolded proteins, including hyper-phosphorylated tau and oligomeric alpha-Synuclein via autophagy. Nilotinib increases the levels of key autophagy proteins like parkin, beclin-1, light chain protein (LC3-I/II), P62, and autophagy like proteins (ATGs) in animal models of neurodegeneration.

Design/Methods CSF was collected as part of an open label phase I (12 participants, 6 months treatment)) and phase II randomized, double-blind, placebo-controlled study with 75 participants randomized 1:1:1 into placebo, 150 mg or 300 mg nilotinib groups. Nilotinib versus placebo was taken orally once daily for 12 months.

Results Next generation whole-genome sequencing of microRNAs in the CSF demonstrated that nilotinib significantly increases (multiple fold with False Discovery Rate <0.001) microRNAs that specifically regulate the expression of autophagy and ubiquitination genes in individuals with PD. No effects were detected on genes that regulate tyrosine kinases, which are the likely protein targets of nilotinib.

Conclusions These data provide robust evidence that nilotinib effects on misfolded protein clearance is via autophagy. CSF microRNA sequencing is a valid biomarker of nilotinib effects on autophagy in a definitive phase III study to investigate nilotinib in PD and other neurodegenerative diseases.

Authors/Disclosures
Charbel E. Moussa, PhD, MB (Georgetown University) PRESENTER	Dr. Moussa has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for KeifeRX LLC. Dr. Moussa has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sun Pharmaceuticals Research Industry. Dr. Moussa has received stock or an ownership interest from Orphan Therapeutics. The institution of Dr. Moussa has received research support from NIA. The institution of Dr. Moussa has received research support from Sun Pharmaceuticals Research Industry. The institution of Dr. Moussa has received research support from Alzheimer's Association . Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received intellectual property interests from a discovery or technology relating to health care. Dr. Moussa has received publishing royalties from a publication relating to health care. Dr. Moussa has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with DG Information Technology. Dr. Moussa has received personal compensation in the range of $0-$499 for serving as a Peer Reviews with National Institutes of Health.
Alan Fowler	Mr. Fowler has nothing to disclose.
Yasar A. Torres-Yaghi, MD	Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Torres-Yaghi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amneal. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbott. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Kyowa Kirin. Dr. Torres-Yaghi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Teva. Dr. Torres-Yaghi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sunovion .
Fernando L. Pagan, MD, FAAN (Georgetown University Hospital Dept of Neurology)	Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Acorda. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Adamas. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merz. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kyowa Kirin. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for US World Meds. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Adamas. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amneal. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurocrine. Dr. Pagan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Supernus. Dr. Pagan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Parkinsonism and related Disorders. Dr. Pagan has stock in Keiferx. The institution of Dr. Pagan has received research support from US World Meds. The institution of Dr. Pagan has received research support from Novartis.
	No disclosure on file
	No disclosure on file
Abigail C. Lawler, MD (Inova neurology)	No disclosure on file
Elizabeth E. Mundel, MD (MedStar Georgetown University Hospital)	No disclosure on file
Nadia Yusuf, MD	No disclosure on file
James N. Starr, DO (NGPG Neurology)	No disclosure on file
Muhammad W. Anjum, MD (LSUHSC-S Department of Neurology)	Dr. Anjum has nothing to disclose.
Shahnaz Miri, MD (Wilmer Eye Institute, Johns Hopkins University)	Dr. Miri has received intellectual property interests from a discovery or technology relating to health care.
Steven W. Nakano, MD	Dr. Nakano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kyowa Kirin Group. Dr. Nakano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia Pharmaceuticals.
Amelia Carwin, MD (SCL Health)	Dr. Carwin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Carwin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kyowa Kirin.
	No disclosure on file
	No disclosure on file

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