Huntington’s and Alzheimer’s Disease - New Heterocyclic Compounds to Counteract Protein Misfolding
Reference Number: 09-02
Inventor: Dr. Duy Hua
Background:
K-State researchers have invented a class of compounds called tricyclic pyrones (TP) that may be used as lead compounds for prevention and treatment of multiple neurodegenerative diseases including Huntington’s (HD) and Alzheimer’s Disease (AD).
TP compounds have shown the ability to effectively inhibit aggregation caused by mutant huntingtin protein (mhtt) in neurons and glial cells. Aggregate formation has served as a phenotype in screening of small molecules and peptides for their inhibitory properties that promote cell survival in mhtt-expressing cells including some FDA approved drugs for their ability to prevent aggregation. Although the FDA approved compounds effectively reversed aggregation of amino terminal fragment of mutant huntingtin (1-171) with 58 polyglutamines in vitro, none of these molecules were effective in promoting survival of R6/2 mice, a model representing the most severe HD phenotype. Thus, blocking aggregation formation, by itself, may not be a definite predictor of effective potential therapeutics.
The researchers wanted to investigate other possible predictors for effective therapeutics; therefore, they examined earlier cellular defects that preclude aggregate formation in cells. These early defects include cholesterol accumulation and clathrin-independent endocytosis in HD neurons. All three TP compounds (CP2, TP4, TP3) used in the study showed that they partially restore clathrin-independent endocytosis and effectively reversed mhtt-induced cholesterol accumulation in HD neurons.
Possible Mechanism of Action:
Their observations suggest that TP compounds possess a complex mechanism of action. First, they may act as small molecules that directly bind faulty proteins preventing aggregation and blocking protein-protein interaction. Additionally, they may also affect cholesterol homeostasis by regulating cellular cholesterol efflux.
Status of Research:
In collaboration with Drs. Trushina and McMurry at the Mayo Clinic, in vitro studies have been performed. A manuscript that describes the studies in more detail has been accepted for publication in the BMC Neuroscience journal and may be provided upon request.
In collaboration with Dr. Lee-Way Jin at University of California, Davis, it was found that treatment of 5x (quintuple transgenic) familial Alzheimer’s disease (5xFAD) mice (2 months old), a robust Aβ42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species, respectively (published results: Hong, H. –S.; Rana, S.; Barrigan, L.; Shi, A.; Jin, L. –W.; Hua, D. H. Inhibition of Alzheimer’s amyloid toxicity with a tricyclic pyrone molecule In Vitro and In Vivo. J. Neurochem. 2009, 108, 1097-1108 and Rana, S.; Hong, H. –S.; Barrigan, L.; Jin, L. –W.; Hua, D. H. Synthesis of Tricyclic Pyrones and Pyridinones and Protection of Aβ-Peptide Induced MC65 Neuronal Cell Death. Bioorg. & Med. Chem. Lett. 2009, 19, 670-674. On line:http://dx.doi.org/10.1016/j.bmcl.2008.12.060).
| Figure 1
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Figure 1 - Treatment with CP2 (a TP compound) prevents aggregate formation caused by expression of truncated form of mhtt in neurons and glial cells. A. Transfection with truncated N-terminal form of mhtt with 82 polyglutamines (GFP-HD82) causes formation of aggregates (arrows) in striatal neurons (a) and glial cells (b) from control mice. Expression of htt fragment with 19 polyglutamines (GFP-HD19) does not cause formation of aggregates (e, f). Pre-treatment with 2 μM of CP2 prevents formation of aggregates in cells transfected with GFP-HD82 (c, d). Images of live cells were taken using LSM 510 confocal microscope with 100x oil DIC lens (1.4 na). Scale bar, 10 μm. B. Quantification of aggregate formation in neurons and glial cells from control mice with and without CP2 treatment |
Advantages:
Potential advantages of this IP over current technologies:
- Possible treatment for Huntington’s Disease
- May be more effective at treating neurodegenerative diseases because of a different mechanism of action
Applications
Potential applications of this innovative technology:
- Huntington’s Disease Therapeutic
- Alzheimer’s Disease Therapeutic
- Treatment of other Neurodegenerative Diseases
Patent Status
- Provisional patent application filed in January 2009.
Kansas State University Research Foundation seeks to have discussions with companies that are interested in licensing and/or research collaborations.
Interested parties should contact:
National Institute for Strategic Technology Acquisition and
Commercialization (NISTAC)
2005 Research Park Circle Manhattan, KS 66502
Tel: 785-532-3900 Fax: 785-532-3909
E-Mail: nistac@ksu.edu