Treating Opioid Use Disorder
Declared a public health emergency by the U.S. Department of Health and Human Services in 2017, the opioid crisis has led to an exponential increase in the number of individuals living with opioid use disorder. The most recent information from the National Center for Drug Abuse Statistics reveals that more than 10 million people misuse opioids annually, resulting in an average of 136 opioid overdose deaths every day.
To combat this epidemic, Cummings School of Veterinary Medicine’s Dr. Elizabeth Byrnes, a professor and associate chair in the Department of Comparative Pathobiology, and Tufts University School of Medicine’s Emmanuel N. Pothos, an associate professor in the Department of Immunology and program director of Pharmacology at Graduate School of Biomedical Sciences are working with researchers from Northeastern University to advance a novel gene therapy to treat opioid use disorder.
The multi-principal investigator team—which includes Drs. Barbara Waszczak from Northeastern, Byrnes, and Pothos—was awarded a $6.7 million joint grant from the National Institute on Drug Abuse (NIDA) to fund the project. The project is partly based on research by Dr. Waszczak, a professor of pharmacology, who spent many years working with a protein called glial-derived neurotrophic factor, or GDNF, as a potential treatment for Parkinson’s Disease, a disease that is characterized by the death of dopamine neurons in the brain; and Dr. Pothos’s previous work on central dopamine deficits during chronic opiate use and opiate withdrawal and the effects of GDNF on facilitation of quantal dopamine neurotransmission that codes for opioid drug reward.
In her early studies, Dr. Waszczak delivered the GDNF protein intranasally and found the treatment protected dopamine neurons in a rat model of Parkinson’s Disease. Unfortunately, the GDNF broke down too quickly, limiting its potential use. To correct this issue, she worked with a private company, Copernicus Therapeutics, Inc., to develop a gene therapy that would allow for a sustained increase in brain GDNF. This collaboration led to the development of plasmid GDNF DNA packaged in nanoparticles (pGNDF NPs), which allowed for intranasal delivery of the GDNF gene to the brain.
After delivery, these pGDNF NPs were found to increase the production of GDNF and promote the recovery of dopamine neurons in the brain. A patent on intranasal delivery of Copernicus’ pGDNF NPs for brain disorders was issued jointly to Northeastern and Copernicus in late 2016.
Substance use disorders are also characterized by blunted dopamine signals in the brain, which is how Byrnes and Pothos, who study the neurobiology of substance use disorders, got involved in the project. Byrnes sat on a panel to review a pitch for a research project presented at the Tufts Clinical and Translational Science Institute by Waszczak and Pothos. They were proposing a study using intranasally delivered pGDNF NPs to treat opioid use disorder in an animal model. Byrnes was invited to join the project in 2018 to conduct behavioral studies on opioid intravenous self-administration that could evaluate the efficacy of pGDNF NPs in the prevention of relapse.
“When developing a treatment targeting the brain, the hard part can be getting it in there, so a one-time non-invasive delivery method that results in prolonged treatment is ideal,” says Byrnes, noting that they have intranasally infused pGDNF NPs into the brain of rats who were trained to self-administer the opioid oxycodone and determined that the treatment effectively decreased drug-seeking behavior, which is considered a measure of relapse risk in animals.
“We’re trying to develop a non-opioid treatment that decreases drug craving because the current treatments for opioid use disorder, like methadone or suboxone, replace one opioid drug with another.”
The research team aspires to create something that would help maintain recovery by decreasing drug craving, which they hypothesize is due to a reversal of decreased dopamine release caused by chronic opioid use. This potential mechanism is being examined in the laboratory of Dr. Pothos, who studies changes in dopamine release dynamics in the animals generated in the Byrnes lab.
“We are testing the hypothesis that intranasal treatment with pGDNF nanoparticles at least partially reverses chronic mesolimbic dopamine deficits. This is a mechanism that can potentially benefit the treatment of several addictive disorders that induce dopamine deficiencies in the brain. The treatment may also benefit other neurotransmitter systems.” Pothos says.
Upon successful completion of this initial phase of research, the team could be eligible to receive three additional years of funding from NIDA, approximately $7.5 million, to conduct the IND-enabling studies and move swiftly into a clinical trial. “If it works, it could be a breakthrough in the treatment of opioid use disorder,” says Byrnes, and a significant upgrade over current treatments, as this could have longer-lasting effects for those undergoing treatment.
“Many individuals who have substance use disorder don’t want to continue taking drugs, yet there is a compulsive drive to do so,” Byrnes says. “If you’ve ever been deprived of something, such as when you’re on a diet, you suddenly can’t stop thinking about food and that feeling can even compel you to seek a delicious treat. We want to decrease that feeling, so that people with an opioid use disorder are not being driven to seek out the drugs again, especially for those who are trying to maintain long-term abstinence.”
Department:Dept. of Comparative Pathobiology