# Dendrimer-conjugated nSMase2 inhibitor as a novel therapeutic approach for Alzheimer's Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $378,916

## Abstract

The number of people suffering from Alzheimer's disease (AD) is steadily rising and current treatments only
provide minor symptom amelioration. Results from recent clinical trials targeting amyloid-β (Aβ) production or
clearance were disappointing, prompting a reexamination of approaches to AD treatment. Brains from AD
patients exhibit accumulation of ceramide, a signaling molecule and an integral component of exosomal
membranes. One major source of ceramide is through the hydrolysis of sphingomyelin catalyzed by neutral
sphingomyelinase 2 (nSmase2). Even though transient increases in ceramide through nSMase2 upregulation
are part of normal brain functioning, experimental evidence indicates that chronic nSMase2 upregulation results
in negative effects including neuroinflammation and oxidative stress. Recent studies implicate nSMase2 in both
Aβ aggregation and tau protein propagation through exosome secretion from glial cells. Moreover, inhibition of
exosome synthesis by genetic or pharmacological inhibition of nSMase2 was shown to block Aβ aggregation
and tau propagation in both in vitro and in vivo AD models, thus opening a new avenue for AD therapeutics.
Unfortunately, there are no clinically useful nSMase2 inhibitors. Current inhibitors are weak (µM-mM) with poor
physicochemical properties and/or limited brain penetration. In collaboration with NCATS we carried out a human
nSMase2 high throughput screen (HTS) of >350,000 compounds. Filtering and analysis of HTS hits led to
discovery of 2,6-dimethoxy-4-(5-phenyl-4-(thiophen-2-yl)-1H-imidazol -2-yl) phenol (DPTIP) the first nM inhibitor
(IC50 = 30 nM). DPTIP was found to be selective and capable of dose-dependently inhibiting exosome release
in glial cultures. Unfortunately, in vivo DPTIP exhibited rapid clearance resulting in a short half-life (t1/2< 0.5h)
and had poor oral bioavailability (F<5%). Structural modifications (~200 analogs synthesized by our group) have
not led to substantial improvements. Given its significant clinical potential, we propose to address the
pharmacokinetic limitations by utilizing dendrimer nanoparticles to deliver DPTIP selectively to activated glial
cells in the brain. Our team discovered that systemically-administered hydroxyl-terminated poly(amidoamine)
(PAMAM) dendrimers (~4 nm in size) target activated glia in the injured brain, without the need for targeting
ligands, showing minimal uptake in healthy brains. While the dendrimers are endocytosed and retained by
activated glial cells in the brain maintaining exposure for >2 weeks, they are rapidly cleared from the periphery
(plasma t1/2 ~ 6-24 h). We have validated the brain targeting, safety, and efficacy in multiple small and large
animal models, and are in Phase 1 clinical trials with our first dendrimer product (D-NAC in childhood
cerebral adrenoleukodystrophy). Herein, we propose to synthesize and evaluate the in vivo
pharmacokinetics and target engagement of two differently sized dendrimers conjugated to ...

## Key facts

- **NIH application ID:** 9970924
- **Project number:** 1R01AG063831-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Rana Rais
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,916
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970924

## Citation

> US National Institutes of Health, RePORTER application 9970924, Dendrimer-conjugated nSMase2 inhibitor as a novel therapeutic approach for Alzheimer's Disease (1R01AG063831-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970924. Licensed CC0.

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