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Develop a novel strategy to deliver N-acetylcysteine for AD treatment

Award Number: R41AG087769
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Develop a novel strategy to deliver N-acetylcysteine for AD treatment - PROJECT SUMMARY After decades of intensive research and drug development efforts, there are still no cures or substantially effective treatments for Alzheimer’s disease (AD). Currently available medications, including cholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aβ) monoclonal antibodies (mAbs), can only reduce certain symptoms or slightly slow down disease progression in mild to moderate AD patients; and their side effects, particularly those of Aβ mAbs, further limit their benefit. The most recently reported efficacy and safety profile of another Aβ mAb donanemab does not add much enthusiasm to the field. Studies of AD have been mainly focused on Aβ plaques and tau protein-formed neurofibrillary tangles in the brain. However, in recent years, it is increasingly clear that the development of AD is the collective consequence of the toxicities induced by Aβ plaques, tau protein-formed neurofibrillary tangles, and malfunctions of microglia. Nacetylcysteine (NAC) is a derivative of amino acid cysteine; it has been studied for its potential effects on AD, largely due to its antioxidant and anti-inflammatory activities, particularly its beneficial effects on microglia. However, NAC cannot penetrate the BBB and reach the brain sufficiently. To realize NAC’s potential as an AD treatment, we developed a brain targeted NAC delivery system (TN-NAC). Our preliminary data demonstrate that TN-NAC can effectively cross the BBB, quench the elevated ROS, attenuate the activation of microglia, reduce Aβ burden, and eliminate senescent cells in the brain in a 5xFAD mouse model, and improve the performance of the animals in behavior tests. Based on these exciting data, in this Phase I STTR study, we will test the feasibility to develop TN-NAC as a therapy for AD through two specific aims. In SA1 we will evaluate the toxicity and pharmacokinetic properties of TN-NAC in mice. The maximum tolerated dose (MTD) of TN-NAC will be first determined in mice; and then the PK properties of TN-NAC at various doses will be examined. In SA2 we will test the therapeutic efficacy of TN-NAC in a 3xTg-AD mouse model. We will assess the effects of TNNAC on biochemical, pathological, and behavioral alterations in the AD mice. We will also further evaluate the systemic toxicity of TN-NAC in AD mice. The successful completion of the proposed studies will serve as a milestone for the further development effort. A Go/No Go decision will be made based on 1) if TN-NAC can achieve sufficient blood and brain NAC concentrations at a certain dose without causing evident toxicity in mice; and 2) if TN-NAC at that dose can significantly attenuate AD pathology and behavioral impairment in the AD mice. A Go decision will lead us in a STTR Phase 2 study to: 1) using large animal models to find a dose range that can be extrapolated to humans and test the safety and efficacy of TN-NAC for the treatment of AD in a GLP setting using large animal models, and 2) carrying out cGMP manufacturing of TN-NAC for human studies. These studies will enable us to file an IND application to FDA.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $499,441 )
2024	2024	ACEPRE, LLC	6439 GARNERS FERRY	COLUMBIA	SC	29209	RICHLAND	USA	Aging Research	000	1	9/12/2024	NEW	$499,441
														Subtotal = $499,441

Grand Total All Awards = $499,441

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Develop a novel strategy to deliver N-acetylcysteine for AD treatment

Award Number: R41AG087769

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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