This U01 application ("Alzheimer's Disease Drug Development Program", PAR-05-148) from the University of Pennsylvania builds on the recent landmark observations of Virginia Lee and John Trojanowski (U01 investigators) that provide compelling support for the hypothesis that microtubule (MT)-stabilizing agents hold great promise for the treatment of Alzheimer's disease (AD) and related neurodegenerative diseases. Central to this hypothesis is the understanding that the MT-stabilizing tau proteins of the central nervous system (CMS) are sequestered into filamentous inclusions that are the signature lesions of AD and related tauopathies, thereby compromising the normal function of tau in stabilizing and maintaining MT networks essential for axonal transport and axon survival. The central thrust of this U01 program is therefore to identify and evaluate potential MT-stabilizing agents as novel drug candidates. Critically important issues related to compound selection that will be addressed include systemic toxicity and availability in the CNS. To this end, and in light of the considerable progress made both in the synthesis and biological evaluation of MT-stabilizing agents from different classes of natural products since our original U01 application submitted in February of 2006, epothilones have been identified as lead structures. We therefore propose to synthesize eight to ten (8-10) selected epothilones, that based on our preliminary studies as well as published reports, are either known or expected to be CNS-penetrant, with the overarching aim of identifying compounds through in vitro and in vivo screening programs that will: (A) possess effective brain uptake, (B) increase the stability of MT-networks in postmitotic neurons of the CNS, and (C) possess negligible systemic toxicity. Initial in vitro/in vivo assays have been designed to evaluate efficacy, PK, toxicity and drug-like properties. Successful candidates will then be characterized through in vivo efficacy and tolerability studies in normal mice. The most promising candidates will be subjected to efficacy studies employing two distinct Tg animal models. Finally, development of an effective scale-up synthesis for the most promising candidate will permit execution of additional pharmacokinetic and toxicological studies, in order to identify a viable candidate to advance towards an Investigational New Drug (IND) application.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG029213-05
Application #
8287605
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (M1))
Program Officer
Petanceska, Suzana
Project Start
2008-09-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$591,855
Indirect Cost
$213,177
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Penazzi, Lorène; Tackenberg, Christian; Ghori, Adnan et al. (2016) Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D. Neuropharmacology 105:84-95
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Rey, Nolwen L; Steiner, Jennifer A; Maroof, Nazia et al. (2016) Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease. J Exp Med 213:1759-78
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Delépine, Chloé; Meziane, Hamid; Nectoux, Juliette et al. (2016) Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes. Hum Mol Genet 25:146-57
Pigott, Kara; Rick, Jacqueline; Xie, Sharon X et al. (2015) Longitudinal study of normal cognition in Parkinson disease. Neurology 85:1276-82
Golovyashkina, Nataliya; Penazzi, Lorène; Ballatore, Carlo et al. (2015) Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes. Mol Neurodegener 10:60
Kalia, Lorraine V; Lang, Anthony E; Hazrati, Lili-Naz et al. (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72:100-5
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2014) APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol 71:1405-12
Nuytemans, Karen; Inchausti, Vanessa; Beecham, Gary W et al. (2014) Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease. Mov Disord 29:827-30

Showing the most recent 10 out of 27 publications