MicroRNA as a Novel Therapeutic Target for Pain in Sickel Cell Disease
Date Published March 16, 2026
Project Date 2025-2029
Targeting let-7 microRNA to develop novel therapeutics for chronic pain in sickle cell disease patients
| This Midwestern University–led project, funded by the National Institute of Neurological Disorders and Stroke, investigates let-7 family microRNA (miRNA) as a novel therapeutic target for chronic pain in sickle cell disease (SCD). SCD affects roughly 100,000 Americans, primarily those of African or Hispanic descent, and is characterized by recurrent vaso-occlusion, hemolytic anemia, progressive organ damage, and both episodic crisis pain and persistent chronic pain that remains refractory to current treatments. The overarching goal of the research is to identify molecular and epigenetic mechanisms by which let-7 miRNA contributes to SCD-associated pain and to validate let-7 targeting as a strategy to develop effective pharmacological interventions that improve patient quality of life. The project builds on the research team’s prior work revealing markedly increased expression of neuronal and circulating exosomal let-7 miRNA in mouse models of SCD and in patients with SCD. Let-7, a developmental timing regulator implicated in the fetal-to-adult hemoglobin switch—a key event associated with SCD pathophysiology—has emerged as a promising candidate given its epigenetic role in post-transcriptional regulation of target genes. Preliminary experiments described in the award demonstrate that spinal knockdown of let-7 significantly reverses persistent pain behaviors in a humanized mouse model of SCD, establishing proof-of-concept that modulation of this miRNA can alter pain phenotypes. Methodologically, the investigators have developed robust assays for assessing distinct pain modalities in SCD mice, documenting evoked hypersensitivities such as tactile allodynia, cold and heat hyperalgesia, and, importantly, ongoing spontaneous pain. The latter—continuous pain experienced independent of external stimuli—is frequently reported by patients but remains poorly understood mechanistically. This project therefore aims to characterize let-7’s contributions to both evoked and spontaneous pain states, bridging gaps between molecular mechanisms and clinically significant pain experiences. Specific aims include defining the molecular and epigenetic targets of let-7 in neural tissues relevant to pain processing, determining how altered let-7 expression drives pain behaviors in preclinical SCD models, and evaluating whether targeted modulation of let-7 can serve as a biomarker and therapeutic approach. Successful completion will not only clarify let-7’s role as a mechanism underlying chronic SCD pain but will also provide a scientific foundation for translational research and potential future clinical development. The project aligns with the HEAL Initiative priority of discovering and validating novel targets for safe and effective pain treatment and is structured to generate mechanistic insight, preclinical validation, and biomarker data that could accelerate therapeutic development. By focusing on an epigenetic regulator with demonstrated dysregulation in SCD, the study holds promise to yield new strategies for addressing a major unmet medical need: persistent, intractable pain in people living with sickle cell disease. |
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COM Affiliation
Funding Amount
$1,764,145
Funding Type
Federal Government Award
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