SB1AG056181
Project Grant
Overview
Grant Description
Development of DYRK1A Allosteric Modulator for the Treatment of Alzheimer's Disease - Project Summary
This proposal aims to develop ABI-171, a potent and selective inhibitor of the "Dual-Specificity Tyrosine- (Y)-Phosphorylation Regulated Kinase-1A" (DYRK1A), to treat mild to moderate Alzheimer's disease (AD) because of its role in inflammation and phosphorylation of key target proteins like amyloid precursor protein (APP), presenilin-1 (PS1), and tau.
AD is a neurodegenerative disorder characterized by neuronal death and loss of gray matter in the frontal cortex and hippocampus. Memory loss is a typical symptom of AD and has been linked to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs).
A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD; they participate in forming NFTs whose presence is closely linked with disease progression. According to the SS-amyloid cascade hypothesis, the deposition of insoluble SS-amyloid is responsible for neuronal death. Plaques are constituted by SS-amyloid peptides (ASS) that are generated via the cleavage of the amyloid precursor protein (APP) by SS- and -secretases.
DYRK1A is a proline-directed serine/threonine kinase for which many proteins are shown as substrate. DYRK1A activity may be involved in AD pathogenesis because (1) it is robustly expressed in CNS neurons; (2) directly attenuate inflammation by targeting NRF2 and GFAP; (3) DYRK1A phosphorylates APP directly and increases the secretase-mediated cleavage of APP into ASS peptides; (4) DYRK1A is a kinase for which tau serves as a substrate and its presence is associated with increased phosphorylation of tau; (5) DYRK1A selective inhibitor ABI-171 is efficacious in a pilot 5XFAD efficacy model, an AD animal model. Significantly, DYRK1A primes tau for additional phosphorylation by GSK3SS kinase, which is known to contribute to AD pathogenesis. (6) DYRK1A phosphorylates PS1, a subunit of -secretase, and this phosphorylation event increases -secretase protease activity, further elevating ASS peptide production.
These findings support our hypothesis that inhibition of DYRK1A activity will be disease-modifying and significantly impact the lives of those with AD. Despite a role for DYRK1A in AD pathogenesis, few pharmaceutical industry efforts target the modulation of this enzyme. Avanti Biosciences is specifically and uniquely focused on discovering negative modulators selectively of DYRK1A in the brain.
This Commercialization Readiness Pilot (CRP) grant will allow us to continue the work from the original grant 1R44AG056181 and enable us to confirm the efficacy of the drug in the treatment of AD, study in more detail its mechanism of action, complete the CMC and safety studies that are necessary to file an IND with the FDA.
In this grant, four specific aims (SA) are proposed: In SA1 we propose studying the molecule in a chronic model of AD in which the mechanism of action is explored. In SA2 we investigate the toxicity of the drug and determine its therapeutic index. In SA 3 we have the chemistry, manufacturing, and control (CMC) activities for IND-enabling pharmacology/toxicology tests. Finally, in SA4 we have the IND enabling studies, including toxicology, safety, and genotoxicity studies.
This proposal will generate all the information needed for filing an IND and move the project to the clinical trial stage.
This proposal aims to develop ABI-171, a potent and selective inhibitor of the "Dual-Specificity Tyrosine- (Y)-Phosphorylation Regulated Kinase-1A" (DYRK1A), to treat mild to moderate Alzheimer's disease (AD) because of its role in inflammation and phosphorylation of key target proteins like amyloid precursor protein (APP), presenilin-1 (PS1), and tau.
AD is a neurodegenerative disorder characterized by neuronal death and loss of gray matter in the frontal cortex and hippocampus. Memory loss is a typical symptom of AD and has been linked to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs).
A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD; they participate in forming NFTs whose presence is closely linked with disease progression. According to the SS-amyloid cascade hypothesis, the deposition of insoluble SS-amyloid is responsible for neuronal death. Plaques are constituted by SS-amyloid peptides (ASS) that are generated via the cleavage of the amyloid precursor protein (APP) by SS- and -secretases.
DYRK1A is a proline-directed serine/threonine kinase for which many proteins are shown as substrate. DYRK1A activity may be involved in AD pathogenesis because (1) it is robustly expressed in CNS neurons; (2) directly attenuate inflammation by targeting NRF2 and GFAP; (3) DYRK1A phosphorylates APP directly and increases the secretase-mediated cleavage of APP into ASS peptides; (4) DYRK1A is a kinase for which tau serves as a substrate and its presence is associated with increased phosphorylation of tau; (5) DYRK1A selective inhibitor ABI-171 is efficacious in a pilot 5XFAD efficacy model, an AD animal model. Significantly, DYRK1A primes tau for additional phosphorylation by GSK3SS kinase, which is known to contribute to AD pathogenesis. (6) DYRK1A phosphorylates PS1, a subunit of -secretase, and this phosphorylation event increases -secretase protease activity, further elevating ASS peptide production.
These findings support our hypothesis that inhibition of DYRK1A activity will be disease-modifying and significantly impact the lives of those with AD. Despite a role for DYRK1A in AD pathogenesis, few pharmaceutical industry efforts target the modulation of this enzyme. Avanti Biosciences is specifically and uniquely focused on discovering negative modulators selectively of DYRK1A in the brain.
This Commercialization Readiness Pilot (CRP) grant will allow us to continue the work from the original grant 1R44AG056181 and enable us to confirm the efficacy of the drug in the treatment of AD, study in more detail its mechanism of action, complete the CMC and safety studies that are necessary to file an IND with the FDA.
In this grant, four specific aims (SA) are proposed: In SA1 we propose studying the molecule in a chronic model of AD in which the mechanism of action is explored. In SA2 we investigate the toxicity of the drug and determine its therapeutic index. In SA 3 we have the chemistry, manufacturing, and control (CMC) activities for IND-enabling pharmacology/toxicology tests. Finally, in SA4 we have the IND enabling studies, including toxicology, safety, and genotoxicity studies.
This proposal will generate all the information needed for filing an IND and move the project to the clinical trial stage.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
San Diego,
California
921211126
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 243% from $976,999 to $3,350,753.
Avanti Biosciences was awarded
Developing ABI-171: A DYRK1A Allosteric Modulator Alzheimer's Treatment
Project Grant SB1AG056181
worth $3,350,753
from National Institute on Aging in August 2017 with work to be completed primarily in San Diego California United States.
The grant
has a duration of 8 years and
was awarded through assistance program 93.866 Aging Research.
The Project Grant was awarded through grant opportunity SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late Stage Development (SB1, Clinical Trial Not Allowed).
SBIR Details
Research Type
SBIR Phase II
Title
Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease
Abstract
PROJECT SUMMARYThis proposal aims to develop ABI-171, a potent and selective inhibitor of the “Dual-specificity tyrosine- (Y)-phosphorylation Regulated Kinase-1A†(DYRK1A), to treat mild to moderate Alzheimer’s disease (AD) because of its role in inflammation and phosphorylation of key target protein like Amyloid Precursor Protein (APP), Presenilin-1 (PS1), and tau.AD is a neurodegenerative disorder is characterized by neuronal death and loss of gray matter in the frontal cortex and hippocampus. Memory loss is a typical symptom of AD and has been linked to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD; they participate in forming NFTs whose presence is closely linked with disease progression. According to the β-amyloid cascade hypothesis, the deposition of insoluble β-amyloid is responsible for neuronal death. Plaques are constituted by β-amyloid peptides (Aβ) that are generated via the cleavage of the amyloid precursor protein (APP) by β- and γ-secretases.DYRK1A is a proline-directed serine/threonine kinase for which many proteins are shown as substrate1. DYRK1A activity may be involved in AD pathogenesis because (1) it is robustly expressed in CNS neurons; (2) directly attenuate inflammation by targeting Nrf2 and GFAP; (3) DYRK1A phosphorylates APP directly and increases the secretase-mediated cleavage of APP into Aβ peptides; (4) DYRK1A is a kinase for which tau serves as a substrate and its presence is associated with increased phosphorylation of tau; (5) DYRK1A selective inhibitor ABI-171 is efficacious in a pilot 5xFAD efficacy model, an AD animal model. Significantly, DYRK1A primes tau for additional phosphorylation by GSK3β kinase, which is known to contribute to AD pathogenesis. (6) DYRK1A phosphorylates PS1 a subunit of γ-secretase, and this phosphorylation event increases γ-secretase protease activity, further elevating Aβ peptide production. These findings support our hypothesis that inhibition of DYRK1A activity will be disease-modifying and significantly impact the lives of those with AD.Despite a role for DYRK1A in AD pathogenesis, few pharmaceutical industry efforts target the modulation of this enzyme. Avanti Biosciences is specifically and uniquely focused on discovering negative modulators selectively of DYRK1A in the brain. This Commercialization Readiness Pilot (CRP) grant will allow us to continue the work from the original grant 1R44AG056181 and enable us to confirm the efficacy of the drug in the treatment of AD, study in more detail its mechanism of action, complete the CMC and safety studies that are necessary to file an IND with the FDA.In this grant, four specific aims (SA) are proposed: in SA1 we propose studying the molecule in a chronic model of AD in which the mechanism of action is explored. In SA2 we investigate the toxicity of the drug anddetermine its therapeutic index. In SA 3 we have the Chemistry, Manufacturing, and Control (CMC) activities for IND-enabling pharmacology/toxicology tests. Finally, in SA4 we have the IND enabling studies, including toxicology, safety, and genotoxicity studies.This proposal will generate all the information needed for filing an IND and move the project to the clinical trial stage.
Topic Code
NIA
Solicitation Number
PAR20-129
Status
(Complete)
Last Modified 9/5/24
Period of Performance
8/15/17
Start Date
8/31/25
End Date
Funding Split
$3.4M
Federal Obligation
$0.0
Non-Federal Obligation
$3.4M
Total Obligated
Activity Timeline
Transaction History
Modifications to SB1AG056181
Additional Detail
Award ID FAIN
SB1AG056181
SAI Number
SB1AG056181-4240391063
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Small Business
Awarding Office
75NN00 NIH NATIONAL INSITUTE ON AGING
Funding Office
75NN00 NIH NATIONAL INSITUTE ON AGING
Awardee UEI
GZNJSM9ELXB3
Awardee CAGE
5MR40
Performance District
CA-50
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute on Aging, National Institutes of Health, Health and Human Services (075-0843) | Health research and training | Grants, subsidies, and contributions (41.0) | $2,216,324 | 100% |
Modified: 9/5/24