If I recall correctly, Ariad has a patent for use of pona in Parkinson's. But until the AE profile is clearer at low doses it would likely never be used.
Here is a discussion of possible mechanism in both AD and PD:
Program#/Poster#: 403.06
Presentation Title: Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance
Location: 32B
Presentation time: Monday, Nov 11, 2013, 2:15 PM - 2:30 PM
Topic: ++C.03.l. Alzheimer's disease: In vivo therapeutics
Authors: *C. E. MOUSSA1, M. HEBRON2, I. LONSKAYA2;
1Biochem, Mol & Cell Biol, Georgetown Univ., WASHINGTON, DC; 2Neurosci., Georgetown Univ., Washington, DC
Abstract: Tyrosine kinase inhibitors are effective therapies for leukemia. Alzheimer is a neurodegenerative disease characterized by accumulation of a-amyloid (plaques) and hyper-phosphorylated Tau (tangles). Here we show that AD animals have high levels of insoluble parkin and decreased parkin-Beclin-1 interaction, while peripheral administration of tyrosine kinase inhibitors, including Nilotinib and Bosutinib, increases soluble parkin leading to amyloid clearance and cognitive improvement. Blocking Beclin-1 expression with shRNA or parkin deletion prevents tyrosine kinase inhibition-induced amyloid clearance, suggesting that functional parkin-Beclin-1 interaction mediates amyloid degradation. Isolation of autophagic vacuoles in AD mouse brain shows accumulation of parkin and amyloid, consistent with previous results in AD brains, while Bosutinib and Nilotinib increase parkin-Beclin-1 interaction and result in protein deposition in the lysosome. These data suggest that decreased parkin solubility impedes parkin-Beclin-1 interaction and amyloid clearance. We identified two FDA-approved anti-cancer drugs as potential treatment for AD.
Disclosures: C.E. Moussa: Other; Dr. Moussa has a provisional patent application to use Tyrosine Kinase Inhibitors as a therapry for neurodegeneration. I. Lonskaya: None. M. Hebron: None.
| Nilotinib, a c-Abl inhibitor, protects dopaminergic neurons from MPTP induced neurotoxicity | |
| Location: | Hall A-C | |
| Presentation time: | Wednesday, Nov 16, 2011, 2:00 PM - 3:00 PM | |
| Authors: | *S. S. KARUPPAGOUNDER1,2, H. S. KO3,4, Y. LEE5,4, S.-X. WANG3,4, V. L. DAWSON4,7, T. M. DAWSON6,4;
1Neuroregeneration and Stem Cell Programs, Inst. for Cell Engineering, Depar, Johns Hopkins Univ. Sch. of Med., Baltimore, MD; 2Neurol., Baltimore, MD; 3Neurol., 5Physiol., 6Neurology, Solomon H. Snyder Dept. of Neurosci., 4Neuroregeneration and Stem Cell Programs, Inst. for Cell Engin., Baltimore, MD; 7Departments of Neurology, Physiology, and Solomon H. Snyder Dept. of Neurosci., Baltimore, MD | |
| Abstract: | Oxidative stress contributes to the pathogenesis of Parkinson’s disease (PD). c-Abl kinase activation is a key indicator of oxidative stress and growing evidence indicates that c-Abl activation is associated with the neuronal death in neurodegenerative disorders. Previously, we have identified that c-Abl is activated in the brain of PD patients and in MPTP intoxicated mice. In addition c-Abl tyrosine phosphorylates parkin, leading to loss of parkin’s E3 ligase activity, inhibition of its protection function and accumulation of its substrates, AIMP2 and FBP1. Moreover, the c-Abl inhibitor, STI-571 restores parkin’s E3 ligase activity and protection function through inhibition of tyrosine phosphorylation of parkin. Conditional knockout of c-Abl in mice protects against MPTP toxicity. Thus, inhibition of c-Abl is an attractive therapeutic target for the treatment of PD. In the present study, we evaluated the in vivo efficacy of the selective c-Abl inhibitor, Nilotinib in the MPTP-induced animal model of PD. Our results show that administration of Nilotinib results in protection of DA neuron loss against MPTP toxicity as well as reduces the initial mortality of MPTP treated mice. This study provides a strong rationale for testing of other c-Abl inhibitors as potential therapeutic agents for the treatment of PD.
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