Advancing Therapeutic Development for Pain and Opioid Use Disorders Through Public-Private Partnerships Proceedings of a Workshop (2018) / Chapter Skim
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3 Exploring the State of the Science and Preclinical Models for Pain Therapeutic Development
3 Exploring the State of the Science and Preclinical Models for Pain Therapeutic Development
Pages 17-28
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From page 17... ...
. • Translating genetically identified targets into therapies and bi omarkers involves multiple steps, moving from association studies to preclinical models to clinical studies (Diatchenko)
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NEURAL CIRCUITS, CELLS, AND MOLECULAR MEDIATORS OF PAIN There have been great advances in understanding pain from a systems and circuitry perspective, as well as the physiology and cell biology of central and peripheral systems mediating pain sensation and behavior, said Tony Yaksh. This understanding now includes the recognition that pain processing involves complex circuitry as well as the involvement of neuronal and non-neuronal cells, synapses, sodium channels, and inflammatory mediators (Woller et al., 2017)
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PRECLINICAL EFFORTS TO IDENTIFY PAIN TARGETS AND TREAT PAIN To gain a better understanding of what is needed for the development of safe, effective, and non-addictive pain treatments, many workshop participants discussed novel methods for identifying targets for pain and considered what might be done to improve target validation. Genetic Approaches for Target Identification and Translation The discovery of genetic variants that are associated with any medical condition provides novel biological insight and potential therapeutic targets and biomarkers, which can be used to advance the development of new treatments, including personalized medicine, said Diatchenko.
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those discoveries into new drugs involves several steps, moving from association studies, to understanding the molecular genetic mechanisms of functional variants, to animal studies demonstrating how the genetic variant contributes to pain in vivo, and finally to clinical trials. Diatchenko
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Disease Modeling in Human Cells, Tissue, and Organoids Clifford Woolf proposed using stem cell–derived neurons for the following purposes: investigating known targets, conducting target-based drug screens, disease modeling to identify mechanistic drivers of pain, identifying individuals at risk of transitioning from acute to chronic pain, conducting phenotypic drug screens, aiding in personalized treatment selection, and conducting in vitro clinical trials. This is possible, he said, by
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combining stem cell technology with CRISPR1 engineering technology, which allows investigators to generate induced pluripotent stem cells (iPSCs) from the fibroblasts of patients with a certain phenotype, characterize neurons grown in culture from those iPSCs, replicate mutations identified in the patient material, and engineer mice to have those same mutations.
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From page 23... ...
He added that iPSCs could also be used to explore the mechanisms that lead to chemotherapyinduced peripheral neuropathy or to other clinical pain syndromes and identify novel agents that protect against those effects. To accomplish this would require analyzing multiple iPSC lines from deeply phenotyped and genotyped patients, stated Woolf.
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This technology and others that have been advanced by the BRAIN Initiative are developing rapidly, said Gereau, enabling the identification of cells and circuits that change in association with the development of chronic pain. Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, questioned the translatability of this approach to human diseases because they are not working with human cells.
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Nonetheless, new approaches are needed to address shortcomings in existing models and to enable longer-term studies, he said. For example, longer-term studies are needed that model chronic inflammatory conditions such as arthritis; that more closely recapitulate the human phenotype; that address spontaneous versus evoked behaviors, thus precluding the need for ongoing handling by investigators; and that enable assessment of reinforcing effects of pain relief, said Yaksh.
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Dorothy Cimino Brown, lead executional scientist for Translational Comparative Medical Research at Elanco, the animal health division of Eli Lilly and Company, runs clinical trials in companion animals, especially dogs. Two types of pain conditions are common in dogs: osteoarthritis and bone cancer.
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Before advancing to companion animals, the drug was tested in rats, where unilateral injection into the trigeminal ganglia was shown to block sensitivity to corneal application of capsaicin, she said. In dogs with osteosarcoma, efficacy was tested using gait analysis, owner assessment, and activity monitoring.
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From page 28... ...
For example, Yaksh noted that companion animals are associated with inherent greater variability because the investigator must rely on the natural development of the pain state. To summarize, Yaksh noted that replicating preclinical findings by encouraging detailed reporting of methods and results, incorporating randomization and blinding into preclinical studies, emphasizing effect size and clinical relevance, and routinely including an active control in preclinical modeling could reduce some of the reproducibility issues of preclinical findings and improve the translatability of those findings to the clinical space.
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