/ Chronic pain is a major healthcare burden, representing economic costs of up to $635B per year, morethan cancer, diabetes, and heart disease, according to a Johns Hopkins study published in the Journal of Pain.Pain is a highly heterogeneous condition comprising neuropathic, nociceptive and inflammatory components,and patient responses to currently available drugs vary greatly. A very promising approach to target various forms of pain is through antagonism of key players in neuro-inflammation. Specifically, the chemokine receptor system, a complex network of over 20 different receptors andover 80 ligands, is integral to neuroinflammatory processes and the pharmaceutical industry had been very activein developing compounds targeting individual receptors in the network. However, the biological complexity,ligand promiscuity, and receptor redundancy of the chemokine receptor system has precluded successful clinicaldevelopment of the compounds and many pharma have exited the pain therapeutic area. A major limitation of successful targeting of this network is sufficient understanding of the molecular andcellular dynamics of the chemokine network, and how specific receptors vary in chronic pain conditions. In thisstudy, we aim to determine the genetic expression of a chemokine receptor utilizing human clinical samplescollected in a clinical trial evaluating a receptor antagonist. Further, we will utilize this understanding inconjunction with patient efficacy data from the clinical trials to continue the development of our lead compound,a drug that showed a statistically significant clinical signal in pain. Results from this study will enable patientstratification and effective clinical trial design by including patients with the appropriate genetic and phenotypicbackground and thus significantly increase the likelihood achieving primary endpoints of pain reduction in theclinic.
Public Health Relevance Statement: Project Narrative
Chronic pain results in suffering, reduced quality of life, and significant healthcare burdens, with an
estimated annual economic cost up to $635B. Neuropathy and neuroinflammatory processes affected by the
chemokine receptor system represent a promising area to treat various forms of chronic pain and these have
attracted large investments in recent years. We aim to develop a deeper biological understanding of the receptor
dynamics in this system using human samples collected from clinical trials evaluating an investigational drug
antagonist for the receptor.
Project Terms: Affect ; Alternative Splicing ; Alternate Splicing ; Alternative RNA Splicing ; Amino Acid Sequence ; Primary Protein Structure ; protein sequence ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Clinical Trials ; Diabetes Mellitus ; diabetes ; Drug Antagonism ; Drug Industry ; Pharmaceutic Industry ; Pharmaceutical Industry ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Investigational Drugs ; Investigational New Drugs ; Heart Diseases ; Cardiac Diseases ; Cardiac Disorders ; heart disorder ; Human ; Modern Man ; Inflammation ; Investments ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligands ; Methods ; Transgenic Mice ; mRNA Precursor ; Pre-mRNA ; RNA, Messenger, Precursors ; premRNA ; Pain ; Painful ; Patients ; Phenotype ; Physicians ; Play ; Product Labeling ; Publishing ; Quality of life ; QOL ; Diagnostic Reagent Kits ; diagnostic kit ; test kit ; Messenger RNA ; mRNA ; Role ; social role ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Work ; Measures ; Treatment outcome ; Healthcare ; health care ; Population Heterogeneity ; diverse populations ; heterogeneous population ; population diversity ; chronic pain ; Journals ; Magazine ; base ; Area ; Clinical ; Phase ; Biological ; Medical ; Serum ; Blood Serum ; Nociception ; nociceptive ; Individual ; monocyte chemoattractant protein 1 receptor ; CCR2 receptor ; MCP-1 receptor ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; chemokine ; Chemotactic Cytokines ; Homologous Chemotactic Cytokines ; Intercrines ; SIS cytokines ; chemoattractant cytokine ; Therapeutic ; Genetic ; Attenuated ; Inflammatory ; tool ; programs ; Complex ; Clinic ; neuropathic ; Neuropathy ; Source ; System ; Chemokine Receptor Gene ; chemokine receptor ; Isoforms ; Protein Isoforms ; Receptor Protein ; receptor ; receptor expression ; success ; economic cost ; Painful Diabetic Neuropathy ; Diabetic Neuralgia ; Sampling ; response ; drug development ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Receptor Gene ; Data ; Grant Proposals ; Applications Grants ; Clinical Data ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Clinical Trials Design ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Molecular ; Knock-out ; Knockout ; Process ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; Development ; developmental ; painful neuropathy ; neuropathic pain ; genetic profiling ; neuroinflammation ; neuroinflammatory ; Outcome ; C-terminal ; inclusion criteria ; therapeutic target ; patient population ; population based ; diabetic patient ; material transfer agreement ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; phase II trial ; phase 2 trial ; companion diagnostics ; patient stratification ; stratified patient ; responders and non-responders ; responders from non-responders ; responders or non-responders ; responders versus non-responders ; responders vs non-responders ; clinical diagnostics ; clinical development ; chronic painful condition ; chronic pain condition ; chronic pain disorder ; pain reduction ; reduce pain ; pain patient ; pain relief ; relieve pain ; patient response ; patient specific response ; responsive patient ; secondary endpoint ; secondary end point ; primary endpoint ; primary end point ; in-vitro diagnostics ;
