[R01] Inflammatory Biosignatures for the Identification of Sickle Cell Associated Pain Phenotypes (IBIS-CAP)
Ente: National Heart Lung and Blood Institute
Scadenza: 2031-05-31
Importo max: 834.899 EUR
Paese: US
Descrizione
Project Summary:
SCD is characterized by a globin mutation that leads to hemolysis, vaso-occlusion, progressive organ
injury, pain and death. Despite recent advances chronic pain remains a major cause of suffering and morbidity,
with poorly understood biology and no targeted treatments. Previous attempts to generate biomarkers for
chronic SCD pain failed, likely because chronic pain is not homogenous, with underlying pathophysiology too
complex to be measured with a single biomarker. Our group, with expertise in chronic pain pathophysiology,
clinical trials design, and proteomic and genomic network modelling, generated preliminary proteomic
signatures, composed of multiple biomarkers, for the three main types of SCD chronic pain: nociceptive (due to
tissue damage and inflammation), neuropathic (pain due to damage to the central and/or peripheral nervous
system) and nociplastic (due to peripheral and/or central sensitization). These signatures were able to
effectively distinguish between different types of SCD chronic pain with a single measurement. Our global
hypothesis is that chronic pain in SCD is heterogenous and that each pain phenotype can be identified using
combinations of biomarkers to form proteomic signatures. Further, we hypothesize that by examining repeated
measures of these signatures over time and including genomic data we can perform a network analysis to
determine drivers of chronic pain phenotypes. We also performed a small double blinded randomized study
where patients with SCD and chronic pain were given dronabinol or placebo for 8 weeks and demonstrated
those who received dronabinol had reduced markers of mast cell activation and improvement in clinical
symptoms, though response was stronger in some patients than others. We believe this may serve as proof of
concept that targeting pathways involved in the signature of each pain type may be effective treatment,
especially for those with chronic pain of that phenotype. To test these hypotheses, we will complete the
following aims: Aim 1: To characterize the proteomic signatures of pain phenotypes in people with SCD.
Aim 2: To determine the effect of dronabinol on chronic pain, and chronic pain subtypes in SCD. Aim 3:
Elucidate candidate mechanisms and potential therapeutic targets underlying pain phenotypes. We will
enroll patients at Icahn School of Medicine at Mount Sinai and Emory University, two of the largest SCD
centers in the United States, into a double-blind placebo-controlled study of 6 months of dronabinol or placebo.
Patients will have proteomic panels drawn at baseline and multiple time points during the study, we will use
these to generate proteomic signatures for each pain type. We will use this data to design a phase III study of
dronabinol to further explore the mechanistic hypothesis that to treat chronic pain in SCD it is necessary to
target the underlying mechanisms of the pain phenotype present. This project is the culmination of K23 funded
work by Dr. Su
Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
PI: Susanna Curtis
Progetto: 1R01HL183340-01A1
Settori: National Heart Lung and Blood Institute
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