Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: Our objective was to examine the effects of broad-based tyrosine kinase inhibition in cerebrospinal fluid biomarkers.
Background: Nilotinib is a broad-based tyrosine kinase inhibitor with highest affinity to inhibit Abelson (c-Abl) and Discoidin Domain Receptors (DDR1/2). Preclinical evidence indicate that Nilotinib reduces the level of brain alpha-synuclein and attenuates inflammation in models of Parkinson’s disease (PD). We previously showed that Nilotinib penetrates the blood-brain-barrier (BBB) and potentially improves clinical outcomes in individuals with PD and Dementia with Lewy Bodies (DLB).
Method: We performed a physiologically-based population pharmacokinetics/pharmacodynamics (popPK/PD) study to determine Nilotinib effects in a cohort of 75 PD participants. Participants were randomized (1:1:1:1:1) into 5 groups (n=15) and received open label random single dose (RSD) 150:200:300:400mg Nilotinib versus placebo. Plasma and cerebrospinal fluid (CSF) were collected at 1, 2, 3 and 4 hours after Nilotinib administration.
Results: The results show that Nilotinib enters the brain in a dose-independent manner and 200mg Nilotinib increases the level f 3,4Dihydroxyphenylacetic acid (DOPAC) and Homovanillic Acid (HVA), suggesting alteration of dopamine metabolism. Nilotinib appears to significantly reduce CSF oligomeric:total alpha-synuclein ratio and plasma total alpha-synuclein. Furthermore, Nilotinib significantly increases the CSF level of triggering receptors on myeloid cells (TREM)-2, suggesting an anti-inflammatory effect.
Conclusion: Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers including dopamine metabolism and alpha-synuclein.
To cite this abstract in AMA style:F. Pagan, M. Hebron, B. Wilmarth, Y. Torres-Yaghi, E. Mundel, N. Yusuf, C. Moussa. Multi-kinase Abelson (c-Abl) and Discoidin Domain Receptors (DDR1/2) inhibitors, Nilotinib, alters CSF soluble TREM2 (sTREM2) in individuals with Parkinson’s Disease [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/multi-kinase-abelson-c-abl-and-discoidin-domain-receptors-ddr1-2-inhibitors-nilotinib-alters-csf-soluble-trem2-strem2-in-individuals-with-parkinsons-disease/. Accessed December 1, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-kinase-abelson-c-abl-and-discoidin-domain-receptors-ddr1-2-inhibitors-nilotinib-alters-csf-soluble-trem2-strem2-in-individuals-with-parkinsons-disease/