Chronic neuropathic pain, which is one of the most common forms of chronic pain, is a highly prevalent condition that dramatically decreases productivity and quality of life; it is often associated with insomnia, anxiety and depression, and does not respond well to existing treatments with >50% of patients who are refractory to current medications. Additionally, many pain relief medications are highly addictive, and may involve numerous issues with withdrawal and risks of overdosing. In 2017, more than 47,000 Americans died from an opioid overdose, according to the Centers for Disease Control and Prevention, causing a National Emergency. Thus, there is an urgent need to develop non-opioid analgesics to treat chronic neuropathic pain. To date, attempts at developing novel analgesics have been and continue to be hindered by high clinical attrition and cross-species translational difficulties, resulting in lack of efficacy in pivotal Phase II clinical studies. A very promising avenue for advancing pain research is provided by the recently-established possibility of performing of studies directly on human sensory neurons. Functional, electrophysiology-based studies of human nociceptive neurons are now possible, allowing the direct phenotypic screening and drug candidate profiling in human tissue- based assays at the preclinical stage. This approach has the potential to overcome many of the limitations associated with cross-species differences encountered when using animal models of pain for the identification and selection of clinical drug candidates. AnaBios has developed a novel translational drug screening platform for the generation of human-relevant data in preclinical pain drug discovery. Over the past 9 years, we have developed methods that enable the recovery and interrogation of hDRG; these technologies allow for studies aimed at advancing knowledge of basic pain biology as well as supporting drug discovery efforts. For preclinical-stage drug development programs it is critical to assess: 1) the potential of a new drug candidate in human-relevant models; 2) the activity in specific pain states; 3) the potency. Our proposal aims at introducing new in vitro models to enable the assessment of potential analgesic activity, directly on human samples, at early preclinical stages. Specifically, the development and qualification of in vitro models of pathological states associated with pain is a central goal of the proposal. The availability of qualified pathological models will provide a highly valuable tools for advancing the development of new non-addictive drugs for the treatment of pain. The utilization of primary human cells in translational research and drug discovery can provide data that are essential for addressing two critical translational challenges: the selection of the dose for first-in-human studies and, the selection of the appropriate patient population for proof of concept pivotal Phase 2 clinical studies. This proposal will advance the development of our novel screening platform and will ultimately help bypass the cross-species translational hurdles which have impeded the progress of pain drug development for decades.
Public Health Relevance Statement: NARRATIVE Chronic pain is a highly prevalent and debilitating condition which requires continual treatments with pain medications however, many pain relief medications are highly addictive, and involve numerous issues with withdrawal and risks of overdosing. Development of alternative novel analgesics continues to be hindered by high clinical attrition, resulting in lack of efficacy in pivotal Phase II clinical studies. AnaBios has developed a novel human-based pain drug discovery platform for the generation of human-relevant and clinically predictive data at the preclinical stage, which will overcome the limitations of the current pain drug discovery strategy.
Project Terms: Address; Advanced Development; Affect; Afferent Neurons; American; Analgesics; Animal Model; Animals; Anxiety; base; Biological Assay; Biology; Bypass; Calcium; Carbamazepine; Cell Culture Techniques; Cells; cellular imaging; Centers for Disease Control and Prevention (U.S.); chemotherapy; chronic neuropathic pain; chronic pain; Classification; Clinical; clinical development; clinical predictors; Clinical Research; Coculture Techniques; commercialization; cytokine; Data; Data Set; Databases; dermatome; Development; Dose; drug candidate; drug development; drug discovery; Drug Screening; effective intervention; effective therapy; Effectiveness; Electrophysiology (science); Elements; Emergency Situation; Exhibits; first-in-human; Future; Gene Expression Profile; Generations; Goals; Human; human tissue; Image; imaging modality; In Vitro; in vitro activity; in vitro Model; Inflammatory; inflammatory pain; Insulin; Knowledge; Lead; Ligands; Low Back Pain; Measurement; Measures; Mental Depression; Methods; Modeling; Neuroglia; neuronal excitability; Neurons; Neuropathy; neurotrophic factor; Nociception; non-opioid analgesic; novel; novel therapeutics; opioid overdose; Outcome; overdose risk; Pain; Pain management; pain model; pain relief; Pain Research; painful neuropathy; Pathologic; patient population; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Physiological; pre-clinical; Process; Productivity; Program Development; Property; Quality of life; Recovery; Refractory; Research; RNA; Sampling; screening; side effect; Sleeplessness; Sodium Channel; Sodium Channel Blockers; species difference; Spinal Ganglia; Technology; Testing; Therapeutic; tool; transcriptome sequencing; transcriptomics; Translational Research; Translations; Trigeminal Neuralgia; Vertebral column; voltage; Withdrawal; Work
