Development of NAV1.1 enhancers to treat alzheimer's disease
Ended Project Grant Awarded Last action
- Award ID
- R44AG071137
- Recipient
-
Cure Network Dolby Acceleration Partners LLC UEI DBDLVC8NB5K3
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $7,746,973
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Funding
-
- $7,297,152.00 Federal
- $449,821.00 Non-federal
- Place of performance
- California, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cndap is developing a new class of drugs, acting through a unique mechanism of action, to reverse early pathophysiological and cognitive alterations in alzheimer's disease (ad). Recent studies indicate that network dysfunction, which includes network hyperactivity, altered oscillatory rhythms, and hyper- synchronized networks, is an early pathogenic event found in preclinical models of ad and in patients with early stages of ad. Network dysfunction contributes to cognitive abnormalities, AB and TAU accumulation, and neurodegeneration. In animal models, network dysfunction can be restored by enhancing inhibitory (gabaergic) interneuron-dependent gamma rhythms via optogenetic/sensory stimulation or genetic overexpression of NAV1.1. This restoration of gamma rhythms in the ad models leads to reduced amyloid and TAU deposition, neurodegeneration, microglia and astrocytic activation, inflammation, neurovascular alterations, ad-induced genome-wide transcriptomics changes, altered oscillatory activity, and cognitive decline. Because overexpression of the sodium channel NAV1.1 by as little as 25% restores gamma rhythms to normal levels in ad models, we are developing small molecule therapeutics designed to safely increase NAV1.1 activity in the brain to treat ad. We have identified several small molecule chemotypes that effectively enhance human NAV1.1 currents in cell lines and interneuron-dependent gamma oscillations in brain slices. Systemic intraperitoneal administration of high doses of a NAV1.1 enhancer in vivo in mice produced no overt toxicity or behavioural side effects but significantly increased endogenous gamma oscillatory activity in wildtype mice, suggesting that our compounds are brain penetrant and may have beneficial effects following systemic administration. In this fast-track sbir grant, we propose to further develop NAV1.1 enhancers to treat ad. In phase 1 studies, we will employ medicinal chemistry and SAR analysis to identify structurally unique, potent and selective NAV1.1 enhancers to expand our chemical composition of matter. Pharmacokinetics and brain bioavailability analyses will be used to select the most active compounds with optimal pharmaceutical properties. Our milestone to achieve to move to phase 2 studies is the identification of at least one structurally novel NAV1.1 enhancer that selectively and significantly increases gamma oscillations EX vivo in brain. Phase 2 studies are designed to establish the EX vivo and in vivo efficacy of our NAV1.1 enhancers to restore network dysfunction in preclinical ad mouse models by their ability to prevent network hypersynchrony and abnormal oscillatory activity, restore genome-wide transcriptomic changes and to reduce cognitive impairment, neuropathology and improve survival to support their future development to treat ad patients.
Transactions
| Action | Federal | Non-federal | Date |
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| Amendment | $0 | $0 | |
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| Amendment | $1,249,502 | $0 | |
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| Amendment | $50,000 | $0 | |
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| Amendment | $1,249,502 | $0 | |
| Amendment | $1,249,502 | $0 | |
| Amendment | $1,249,502 | $0 | |
| Amendment | $449,821 | $0 | |
| Original award | $449,821 | $449,821 |
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Quick answers
Who received award R44AG071137?
R44AG071137 was awarded to Cure Network Dolby Acceleration Partners LLC by National Institute on Aging (National Institutes of Health) on August 15, 2021.
How much is award R44AG071137 worth?
$7,746,973 has been obligated on R44AG071137: $7,297,152 in federal funding and $449,821 in non-federal funding.
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