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AI-Based Discovery Seeks Non-Opioid Pain Drugs

Neuron

(National Institute of General Medical Sciences, NIH)

4 Dec. 2019. A new initiative aims to find non-opioid treatments for chronic pain targeting specific nerve cells that initiate pain sensations. The project undertaken at Harvard Medical School, with affiliated hospitals in Boston and other institutions, is supported by a cooperative agreement with Defense Advanced Research Projects Agency, or Darpa, that includes funding of up to $23.4 million.

The Safe Therapeutic Options for Pain and Inflammation, or Stop Pain, initiative seeks to discover new therapies that relieve chronic pain, but work differently from opioid pain relievers. Abuse of opioid pain drugs continues at rates in the U.S. reaching emergency levels, along with heroin and fentanyl sold on the street. Overdose deaths from these drugs this year number more than 130 per day, according to National Institute on Drug Abuse. A report by the National Academies of Sciences, Engineering, and Medicine in July 2017 spells out the full scope of the crisis beyond overdose deaths, with some 2 million Americans age 12 and older addicted to prescription opioid drugs and another 600,000 addicted to heroin.

The Stop Pain project is led by researchers at Harvard’s Laboratory of Systems Pharmacology that studies the actions of drugs in the body, using more systematic and automated processes to accelerate the discovery of new therapies. Among these tools are mathematical models and algorithms to find new treatments in large databases of biochemical and genomic research findings. Researchers in this project are applying these tools to neuroscience, stem cell biology, and medicinal chemistry.

Peter Sorger, director of the lab and professor of systems pharmacology, leads the Stop Pain project. “We have substantial opportunities today,” says Sorger in a university statement, “to combine new laboratory methods, advanced chemistry, and artificial intelligence and bring those tools to bear on the enormous societal, scientific, and medical challenges of pain management.” One of its tools is the Integrated Network and Dynamical Reasoning Assembler, or Indra, that uses natural language processing and algorithms to build models of gene and protein networks from databases of scientific literature.

Sorger is joined by colleagues at Harvard Medical School, Boston Children’s Hospital affiliated with Harvard, Massachusetts Institute of Technology, and Max Planck Institute for Medical Research in Heidelberg, Germany. The researchers are seeking treatments that act on nociceptor neurons, nerve cells in the peripheral nervous system — outside the brain and spinal cord — that detect potentially damaging stimuli and transform those stimuli into pain signals sent to the brain.

“Our goal is to systematically understand the complex network of molecules controlling the function of pain-sensing neurons and use that knowledge to design drug molecules that hit many targets,” adds Bruce Bean, professor of neurobiology and co-investigator on the project, “with the aim of safely and selectively inhibiting nociceptor function.”

The team expects to screen for small molecule, or low molecular weight, compounds that silence human nociceptor neurons derived from stem cells. The researchers will identify the most promising candidates, then refine or redesign their chemistry to best meet clinical needs. The team will assess the lead candidates for safety and efficacy in preclinical tests and simulations.

The Stop Pain project is part of Darpa’s Panacea program that seeks new treatments for demanding conditions that affect the health and well-being of armed services members. Darpa says the program supports efforts that reflect the complexity of biological and molecular processes, and generate treatments addressing multiple protein targets.

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