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Nilotinib effects in Parkinsons disease and dementia with Lewy body
2nd International Conference on Parkinson’s Disease & Movement Disorders
Charbel Moussa, Fernando Pagan, Michaeline Hebron, Ellen H Valadez, Yasar Tores-Yaghi, Xu Huang, Reversa R Mills, Barbara M Wilmarth,
Hellen Howard, Connell Dunn, Alexis Carlson, Abigail Lawler, Sean L Rogers, Ramsey (Drew) Falconer, Jaeil Ahn and Zhaoxia Li
Georgetown University Medical Center, USA
MedStar Georgetown Hospital, USA
Cancer and neurodegeneration include a group of diseases that are mechanistically distinct but may share common
therapeutic targets. Autophagy is a common quality control mechanism shared by mitotic and post-mitotic cells and
it can be exploited to accelerate clearance of unwanted oncogenes and reduce accumulation of toxic proteins in cancer and
neurodegeneration respectively. Tyrosine kinase inhibition is a therapeutically relevant strategy that can induce autophagy.
Our laboratory investigates TKIs that activate autophagy and are FDA-approved for cancer, thus significantly reducing research
and development efforts and cost by re-purposing. In neurodegeneration, the non- receptor tyrosine kinase ABL is activated.
Nilotinib and bosutinib are second generation BCR-ABL and SRC (short for Sacoma)-ABL inhibitors, respectively, that are
therapeutically used for individuals with leukemia. A fraction of nilotinib and bosutinib crosses the blood-brain barrier (BBB),
inhibits ABL and facilitates autophagic misfolded protein clearance, leading to neuroprotection and improved cognition and
motor behavior. Mice treated with a much lower dose of these drugs (< 25% of the typical leukemia dose) show significant
motor and cognitive improvement and degradation of misfolded proteins, leading to normal cell survival. We evaluated the
effects of low doses of Nilotinib, on safety and pharmacokinetics in Parkinson�s disease dementia or dementia with Lewy
body. Twelve subjects were randomized into 150 mg (N=5) or 300 mg (N=7) groups and received oral daily doses of nilotinib
for 24 weeks. The primary objectives were safety and tolerability; pharmacokinetics and target engagement were secondary,
while clinical outcomes were exploratory. This study shows that 150 mg and 300 mg daily doses of nilotinib are safe and well
tolerated in advanced Parkinson�s disease. Nilotinib is detected in the CSF and seems to engage the target via Abl inhibition.
Parkinson-related CSF biomarker, including homovanillic acid is significantly increased, DJ-1 is reduced and �±-synuclein is
stable between baseline and 24-week nilotinib treatment. Exploratory cell death biomarkers including neuron specific enolase
and tau are also reduced. Motor and cognitive performance suggests stabilization of clinical outcomes. These data support the
potential of TKIs in the treatment of PD.