Funded Projects

Opioid use and addiction affects more than 2 million Americans and contribute to a large proportion of all drug overdose deaths. Current treatments for opioid use disorder (e.g., methadone and buprenorphine) are not always effective, may be misused, and can have side effects that discourage treatment continuation. Therefore, Cerevel Therapeutics is evaluating a novel compound, CVL-936, which targets brain molecules called dopamine D3 receptors. These receptors are involved in the brain’s reward and relapse pathways and are present in higher levels in people with addictions. In animal studies, the molecule reduced self-administration of nicotine and fentanyl, including in relapse situations. The project will test the safety and tolerability of CVL-936 in animals and healthy humans and will examine its effectiveness in reducing craving in people with opioid use disorder.

This project aims to develop a new way to stimulate the delta opioid receptor to treat withdrawal and abstinence from chronic opioid use. Withdrawal can cause pain, depression, and anxiety, which contribute to relapse. The research will test promising drug candidates in animal models with the intention of bringing at least one effective and safe compound to the final stage of drug development before human clinical trials can begin.

Fentanyl and its analogs are synthetic opioids that are 100 to 10,000 times more potent than morphine. Overdose from these opioids is extremely dangerous due to their ultra-potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose. This research study will develop novel mu opioid receptor antagonists that bind to the same receptor as the opioid drugs and specifically counteract fentanyl and its analogs, thereby reversing the drugs’ acute toxicity more effectively and with fewer side effects than current treatments. The researchers will characterize novel fentanyl derivatives, identify promising compounds, and pursue preclinical development of these compounds as novel reversal agents against the acute toxicity of fentanyl. The goal is to file an Investigational New Drug application with the U.S. Food and Drug Administration.

In collaboration with Eolas Therapeutics and the NIH Blueprint Neurotherapeutics Network, AstraZeneca has developed a novel compound for treatment of opioid use disorder, AZD4041, which targets orexin 1 (OX1) receptors in the brain. In animal studies, AZD4041 reduced the motivation to consume opioids or nicotine, reduced relapse-like drug-seeking behaviors, and showed a favorable safety profile. The compound also has proven to be safe in an initial Phase 1 clinical trial in healthy human volunteers. This project will further evaluate the safety (e.g., respiratory depression profile) of AZD4041 in human volunteers, using multiple and increasing doses. Upon successful completion of these studies, the compound will be tested in a proof-of-concept efficacy study in patients with opioid use disorder. If this is successful, the compound will advance to larger Phase 2 and Phase 3 pivotal clinical trial to tests its effectiveness in the treatment of opioid use disorder.

The widespread availability of fentanyl and other potent synthetic opioids has dramatically increased opioid-related fatal overdoses. This project will develop and manufacture immune molecules (monoclonal antibodies) to reverse and treat overdose from fentanyl by keeping it out of the brain. This research will advance promising results in animal studies (preventing and reversing fentanyl- and carfentanil-induced breathing problems and irregular heartbeat) to clinical testing in people with opioid use disorder and others at high risk of opioid overdose from accidental or deliberate exposure to fentanyl and fentanyl-like drugs.

Difficulty breathing is a hallmark symptom of an opioid-related overdose and can result in permanent brain injury or death within minutes. This project will develop a community-deployable Automated External Respiration System device that can restore and sustain breathing in people experiencing opioid-induced respiratory depression. The device stimulates the phrenic nerve in the chest that controls breathing until other medical interventions are available or the patient recovers. The research will develop and validate the automated external respiration system for testing in human research participants and ultimately aims to develop a system usable in a community setting.

The sodium channel NaV1.8 is a promising target for the development of effective, non-addictive pain medications. Recent evidence from clinical studies indicates that medications that target NaV1.8 are effective at managing postoperative, neuropathic, and inflammatory pain, but with side effects and prohibitively high cost. This project will test the safety and compatibility in the body of an NaV1.8-targeted molecule, toward developing an effective, non-addictive, once daily oral medication for the treatment of acute postsurgical pain and chronic neuropathic. 

Buprenorphine is an effective treatment for opioid use disorder, but its use is limited due to the need for frequent dosing. This project will optimize the molecular features of an injectable, biodegradable, long-acting (3-month) buprenorphine implant that would not require surgical removal. The research aims to advance toward testing in human research participants.

There is an urgent need for longer acting opioid overdose reversal medications to treat acute fentanyl intoxication and overdose. This project will develop a novel molecule (CS-1103) that sticks to fentanyl and removes it from the body. Previous research with animal models shows that CS-1103 has several features that make it attractive for a new medication. It can reverse fentanyl-induced respiratory depression, preventing another overdose; work in combination with naloxone; and appears to be safe and well-tolerated. The research will continue exploration of CS-1103 toward testing CS-1103 in human research participants.

Drug checking services provide individuals who use drugs with information about the true contents of their purchases, and thus may help prevent overdoses. However, current technologies are either costly, technically complex, and non-portable or subject to false signals and restricted in their detection capabilities. This project will continue development of a new, simple-to-use, point-of-care analytical technology (DoseCheck) that can rapidly detect established drug threats in a sample and recognize newly emerging drugs. The project will also attempt to adapt DoseCheck to provide rapid results in emergency overdose situations and improve the analytical capabilities of medical examiners in under-resourced jurisdictions.

The research team developed an in vitro multi-component joint on a chip (microJoint), in which engineered osteochondral complexes, synovium, and adipose tissues were integrated. This study will introduce sensory innervation into the microJoint and a neuron-containing microfluidic ally will be developed to innervate the microJoint. The osteoarthritis (OA) model will be created in the Neu-microJoint system. The research team will assess activation and/or sensitization of nociceptive afferents with electrophysiology, as well as neurite outgrowth. They will mechanically insult the Neu-microJoint and assess the emergence of “pain” in response to prolonged mechanical stress. Researchers will assess the impact of drugs used clinically for management of OA on OA models and will then use “omic” approaches to identify new biomarkers and therapeutic targets. Researchers will assess the impact of opioids—which they hypothesize will increase the rate of joint degeneration and potentiate the release of pain-producing mediators—on neural activity in the presence and absence of joint injury, as well as the integrity of all joint elements.

Researchers will develop an innovative three-dimensional (3D) model of acute and chronic nociception using human induced pluripotent stem cell (hiPSC) sensory neurons and satellite glial cell surrogates. They will develop a tissue chip for modeling acute and chronic nociception based on 3D hiPSC-based dorsal root ganglion tissue mimics and a high-content, moderate-throughput microelectrode array. Researchers will demonstrate stable spontaneous and noxious stimulus-evoked behavior in response to thermal, chemical, and electrical stimulation challenges. They aim to demonstrate sensitivity to translational control via ligand receptor interactions between neuronal and non-neuronal cell types. They also will demonstrate the quantitative efficiency and preclinical efficacy of our system by detecting known ligand-based modulators of translational control and voltage-gated ion channel antagonists in a sensitized model of chronic nociception. Researchers will leverage the high-throughput nature of our tissue chip model to screen Food and Drug Administration–approved bioactive compounds.