There currently is no drug available that stops the progression of Alzheimer's disease (AD). The abnormal accumulation of neurotoxic brain ss-amyloid peptides (A?) is thought to be a possible cause the disease. A? are produced by proteolytic cleavage of a larger amyloid precursor protein by proteases, called ?- and ?-secretases. Inhibiting 2-secretase cleavage is an attractive approach to reducing A? accumulation and ?-secretase inhibitors are thought to potentially effective for slowing the progression of the disease. We have found a compound, E64d, which improves spatial memory deficit and reduces brain plaque, A? and CTF? in a transgenic AD mouse when intracerebroventricularly (icv) administered. Moreover, E64d also reduces brain A? in the regulated secretory pathway in the guinea pig model of human A? production. The reduction in CTF? and A? in the regulated secretory pathway suggests that E64d may act by inhibiting ?-secretase activity in that pathway. Previously, others found that oral E64d administration safe to use in clinical trials. Thus, E64d is both efficacious in AD animal models and safe to use in humans and therefore has potential as an AD therapeutic. E64d is an ester prodrug of its biologically active acid form, E64c, which is a specific inhibitor of cysteine proteases. E64d is rapidly hydrolyzed to E64c in vivo. However, icv E64d administration is not a therapeutically acceptable route and oral E64d administration results in low brain doses, which is due to hepatic E64c uptake prior to reaching the brain. Therapeutically acceptable and efficacious routes of E64d administration need to be developed in order to advance E64d as an AD therapeutic. This grant will explore various routes of E64d administration and determine their efficacy and brain dose responses in AD animal models. If a suitable route is found, this work will allow the clinical development of a very promising AD therapeutic to proceed.

Public Health Relevance

The relevance of this project to the public health is the development of new and effective Alzheimer's disease drug. Currently, there is no effective means of stopping the progress of this devastating disease and there is an urgent need for new drugs that do so. This project may result in a new Alzheimer's disease treatment that may halt or, possibly, reverse the progression of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
3R44AG032784-03S1
Application #
8318932
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (11))
Program Officer
Buckholtz, Neil
Project Start
2008-09-30
Project End
2013-02-28
Budget Start
2011-09-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2011
Total Cost
$58,511
Indirect Cost
Name
American Life Science Pharmaceuticals
Department
Type
DUNS #
170560960
City
San Diego
State
CA
Country
United States
Zip Code
92109
Hook, Gregory; Jacobsen, J Steven; Grabstein, Kenneth et al. (2015) Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate. Front Neurol 6:178
Hook, Gregory R; Yu, Jin; Sipes, Nancy et al. (2014) The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury. J Neurotrauma 31:515-29
Hook, Gregory; Yu, Jin; Toneff, Thomas et al. (2014) Brain pyroglutamate amyloid-? is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J Alzheimers Dis 41:129-49
Hook, Vivian; Funkelstein, Lydiane; Wegrzyn, Jill et al. (2012) Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease. Biochim Biophys Acta 1824:89-104
Kindy, Mark S; Yu, Jin; Zhu, Hong et al. (2012) Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing A?PP containing the wild-type ?-secretase site sequence. J Alzheimers Dis 29:827-40
Hook, Gregory; Hook, Vivian; Kindy, Mark (2011) The cysteine protease inhibitor, E64d, reduces brain amyloid-? and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, ?-secretase activity. J Alzheimers Dis 26:387-408
Hook, Vivian; Hook, Gregory; Kindy, Mark (2010) Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer's disease. Biol Chem 391:861-72
Hook, Vivian Y H; Kindy, Mark; Reinheckel, Thomas et al. (2009) Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochem Biophys Res Commun 386:284-8
Hook, Vivian; Schechter, Israel; Demuth, Hans-Ulrich et al. (2008) Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease. Biol Chem 389:993-1006