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

> **NIH NIH R41** · ACEPRE, LLC · 2024 · $499,441

## Abstract

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 cGM...

## Key facts

- **NIH application ID:** 11012575
- **Project number:** 1R41AG087769-01A1
- **Recipient organization:** ACEPRE, LLC
- **Principal Investigator:** Daping Fan
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,441
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11012575

## Citation

> US National Institutes of Health, RePORTER application 11012575, Develop a novel strategy to deliver N-acetylcysteine for AD treatment (1R41AG087769-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11012575. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*