# Pharmacologic Inhibition of NLRP3 Inflammasome-Dependent Injury following Vaso-occlusion in Sickle Cell Disease

> **NIH NIH R43** · MIND BIOSCIENCES LLC · 2021 · $295,247

## Abstract

Sickle cell disease (SCD), a devastating chronic inherited disorder caused by a single amino acid substitution in
hemoglobin (Hb), affects approximately 100,000 Americans and millions worldwide. Structurally abnormal Hb in
SCD causes red blood cells (RBCs) to become fragile, rigid, and malformed (i.e., sickled). Chronic and excessive
RBC hemolysis and microvascular occlusion in SCD results in a diverse set of adverse pathologic effects,
including persistent release of reactive oxygen species and an exaggerated pro-inflammatory response from
activation of the innate NLRP3 inflammasome pathway. For those suffering from SCD, this can become a vicious
cycle in which a persistent pro-inflammatory state precipitates further microvascular occlusion, and
consequently, contributes to long-standing inflammation and progressive organ dysfunction. Consequently, SCD
patients suffer from a poor quality of life and have a reduced life expectancy. The complex nature of the disease
and its clinical manifestations require therapies that can target downstream pathophysiologic effects, of which
inflammation plays a key role. Although evidence continues to emerge supporting the potential benefit of anti-
inflammatory agents, there are currently no anti-inflammatory drugs approved specifically for the treatment of
SCD. The NLRP3 inflammasome is a large multimeric protein complex that, when triggered by a diverse set of
danger signals, initiates a profound innate inflammatory response by activating caspase-1 and the
proinflammatory cytokine IL-1β. It is clear that excessive drive of the inflammasome pathway plays a key role in
the pathogenesis of SCD. A potent and selective drug targeting NLRP3 inflammasome inhibition would provide
the most robust inflammatory modulation to benefit SCD patients, far above that which can be achieved with
direct inhibition of caspase-1 or IL-1β. The goal of this proposal is to develop our lead therapeutic candidate
YQ128, a highly potent oral inflammasome inhibitor to reduce morbidity and improve the prognosis for SCD
patients. YQ128 is a bona fide lead drug candidate that represents the culmination of multiple rounds of rational
structure-based modification to improve potency, selectivity, and drug-like physiochemical properties of a novel
chemical scaffold that blocks formation of the inflammasome complex by interfering with the interaction between
NLRP3 and its adaptor protein ASC. Based on a significant body of highly encouraging preliminary in vitro and
in vivo data, we have developed a research strategy that will demonstrate proof-of-concept efficacy for this novel
approach in a model of microvascular occlusion in transgenic SCD mice. This Phase I study will facilitate a rapid
transition to definitive efficacy testing and IND-enabling toxicology studies in Phase II.

## Key facts

- **NIH application ID:** 10258844
- **Project number:** 1R43HL158441-01
- **Recipient organization:** MIND BIOSCIENCES LLC
- **Principal Investigator:** David Richard Light
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $295,247
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258844

## Citation

> US National Institutes of Health, RePORTER application 10258844, Pharmacologic Inhibition of NLRP3 Inflammasome-Dependent Injury following Vaso-occlusion in Sickle Cell Disease (1R43HL158441-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10258844. Licensed CC0.

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