MicroRNA as a Novel Therapeutic Target for Pain in Sickle Cell Disease

Our long-term goal is to develop effective pharmacological interventions that can alleviate sickle cell pain and improve the quality of life for patients with sickle cell disease (SCD). Approximately 100,000 Americans– primarily African or Hispanic background–suffer from SCD, featured with recurrent episodes of acute vaso- occlusion, hemolytic anemia, and progressive organ damage. Patients with SCD endure frequent episodes of acute crisis pain, as well as persistent, intractable chronic pain throughout their lives. Chronic pain in SCD is refractory to current medications and represents a significant unmet medical challenge. There remains a critical and urgent need to identify novel therapeutic targets for effective pain management in SCD. With a growing appreciation for its functional capacity, microRNA (miRNA) is now recognized as one of the major epigenetic regulators that controls target gene expression at the post-transcriptional level. Our group has dedicated significant research effort to investigate the functional role of miRNA in chronic pain conditions, with a focus on let-7 family microRNA (miRNA). As a developmental timing regulator, let-7 miRNA has been implicated in the fetal-to-adult hemoglobin switch– a critical event associated with the onset of sickle cell pain. Meanwhile, results from our preliminary experiments have demonstrated markedly increased expression of neuronal and circulating exosomal let-7 miRNA in mouse models of SCD, as well as patients with SCD. Prior to our study, it was not known whether targeting let-7 miRNA could alleviate chronic pain in SCD. Strikingly, we have since generated preliminary data that spinal let-7 knockdown significantly reversed persistent pain behaviors in a humanized mouse model of SCD. Moreover, we have established robust methodologies to assess different pain types in mice with SCD. Our studies have revealed the presence of evoked hypersensitivity (tactile allodynia, cold and heat hyperalgesia) and, more importantly, ongoing spontaneous pain in multiple mouse models of SCD. Despite being the chief complaint reported by patients with SCD, mechanistic understanding of ongoing spontaneous pain associated with SCD remain largely unexplored. Based on our preliminary findings and the intriguing properties of let-7 miRNA, we will test the hypothesis that let-7 family miRNA can be a novel therapeutic target for chronic pain in SCD. By identifying molecular and epigenetic mechanisms of let-7 miRNA in sickle cell pain, specific targeting of these mechanisms holds great promise of designing effective pain therapies that can benefit patients with SCD. Successful completion of the study will not only characterize the role of let-7 miRNA as a mechanism, biomarker, and therapeutic target for chronic pain in SCD, but also build up a strong scientific framework for future studies that may ultimately lead to additional translational research.