SBIR-STTR Award

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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
There Are No Thesaurus Terms On File For This Project.

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.

Public Health Relevance Statement:
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. Public

NIH Spending Category:
Aging; Alzheimer's Disease; Brain Disorders; Neurodegenerative; Neurosciences

Project Terms:
Acids; Active Sites; Alzheimer's Disease; Amyloid beta-Protein Precursor; amyloid peptide; Animal Experiments; Animal Model; Animals; Asses; base; Behavior; Binding; Biological Availability; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Carotid Arteries; Cathepsins B; Cattle; Cavia; Child; Chromaffin Cells; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Collaborations; cost; cost effective; Cyclodextrins; Cysteine Protease; Cysteine Proteinase Inhibitors; Data; Development; Dimethyl Sulfoxide; Disease; Disease Progression; Dose; Double-Blind Method; Drug Formulations; Drug Kinetics; Esters; Evaluation; Excipients; Expressed Sequence Tags; Funding; Goals; Government; Grant; Health; Hepatic; Housing; Human; Hydrolysis; improved; in vivo; Infusion procedures; inhibitor/antagonist; Injection of therapeutic agent; Intravenous; Japan; Japanese Population; Journals; Kidney; Label; Liver; London; male; Measures; Memory impairment; Modeling; Monkeys; morris water maze; mouse model; Mus; Muscular Dystrophies; Mutation; neurotoxic; Nose; Oral; Oral Administration; Paper; Pathology; Pathway interactions; Patients; Penetration; peptide A; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; pre-clinical; Procedures; Prodrugs; Production; programs; Public Health; public health relevance; Publishing; Research; research study; response; Route; secretase; Secretory Vesicles; Senile Plaques; Site; Social Welfare; Solutions; Sulfhydryl Compounds; Testing; Therapeutic; Tissues; Toxicology; Transgenic Mice; transgenic model of alzheimer disease; Transgenic Organisms; Translating; uptake; volunteer; Work; young ad