A novel gene therapy approach for combating opioid use disorder

Among the most persistent issues that plagues our society is the ongoing opioid epidemic. Opioids like heroin, fentanyl, and prescription pain relievers are constantly in the news as people use them and suffer the adverse effects of addiction. Combating the epidemic is an ongoing effort, with many different solutions being used in conjunction to curb the crisis. At Northeastern, one researcher is working on an innovative approach to tackle this problem.

Barbara Waszczak is a Professor of Pharmacology at Northeastern University. Waszczak is currently leading research on a project that aims to treat opioid use disorder via a novel gene therapy. The National Institute on Drug Abuse (NIDA) recently awarded a joint grant worth $14.7 million to Northeastern and Copernicus Therapeutics, Inc., a biotech company whose cDNA nanoparticles are being used in the project. The project revolves around the use of glial cell-derived neurotrophic factor, or GDNF, which has the ability to promote the recovery of dopamine neurons in the brain (a.k.a. the pleasure center). By placing the cDNA for GDNF within nanoparticles from Copernicus, the GDNF could be sent directly to those neurons in a non-invasive way – specifically, via intranasal delivery. This novel approach using intranasal GDNF nanoparticles could potentially make recovery for opioid users a more streamlined process, with no need for surgery or injections. However, getting to this point was a bit more complicated, as an interesting turn led Waszczak to jump from one project to another.

Prior to her work on opioid use disorder, Waszczak first began working with intranasal GDNF to treat Parkinson’s Disease. The work done had shown that intranasal GDNF protected dopamine neurons from damage in a rat model of Parkinson’s Disease, suggesting it might help slow the progression of the disease in humans. However, this method of applying GDNF wasn’t efficient, as the GDNF would rapidly break down soon after being administered. In response to this, Waszczak developed the method of intranasal delivery of DNA nanoparticles for GDNF that made the overall process much easier. Her partnership with Copernicus allowed her to use their cDNA nanoparticles, which were able to carry the gene for GDNF directly into the brain through the intranasal pathway from nose to brain. “These nanoparticles get into the brain and increase the production of GDNF, rather than just delivering GDNF itself and watching it degrade very quickly,” she notes.  Unfortunately, industry interest in GDNF for Parkinson’s began to wane. While Waszczak was working on her novel approach to the issue, others in the field were having less success with surgical infusions of GDNF in Parkinson’s patients. This led to grant funding for GDNF and Parkinson’s research being greatly reduced. This wasn’t the end of Waszczak’s work however, and she took a different direction. She made the connection that GDNF could potentially be used to treat similar disorders that affect brain dopamine neurons – notably, opioid use disorder.

Currently, there are a number of existing methods to help those suffering from opioid use disorder, one of which is medication-assisted therapy (MAT). MAT works by giving patients specific drugs (that are often a type of opioid themselves) that essentially work as a substitute to help them stay off of dangerous opioids. While MAT can be effective at weaning patients off dangerous drugs, it doesn’t fully curtail the issue. “There are really no drugs that can stop patients from wanting to return to these opioids – they’re still very likely to relapse,” Waszczak says. Opioid drugs work by triggering the dopamine neurons in the reward circuit of the user’s brain, and chronic overuse eventually leads to dopamine-deficiency. This will, in turn, lead the user to crave more of the drug. This is where Waszczak’s work comes into play; by using the GDNF gene therapy, the dopamine neurons will be able to recover from the deficit. “The hypothesis of our study is if they stop having a dopamine deficit, they will have less craving and thus less tendency to relapse.” Instead of replacing the opioids, the GDNF gene therapy would make them no longer want opioids at all.

Moving from hypothesis to testing can be an arduous process not only due to the work involved, but also due to the challenges involved in securing funding for a project. Luckily, Waszczak was able to find the support she needed to kickstart her project.  Shortly after describing her work at a RISE event at Northeastern, she began working with Northeastern’s Center for Research Innovation (CRI) to file a patent application on intranasal delivery of Copernicus’s cDNA nanoparticles for brain disorders. “It was very generous of them to support this patent and pay for the cost of filing,” she says. In November of 2016, the patent was issued jointly to Northeastern and Copernicus.

With the technology secured, it became a matter of finding funding. Following the backing of an early grant from the Brain Research Foundation, Waszczak’s preliminary tests on rats were a success; rats that associated a certain place with the rewarding effects of opioids would no longer return to that place once treated with the intranasal GDNF DNA nanoparticles. These early tests gained Waszczak’s work more recognition in the field of addiction science.

Soon after, she found a second sponsor in the Tufts Clinical Translational Science Institute. With the awards from these two foundations, Waszczak was able to gather the preliminary data on rats that attracted the attention of NIDA, resulting in the recent $14.7 million grant she received. Thanks to that funding, and the support of the CRI, she has been able to continue to accelerate her innovation.

For Waszczak, this support ultimately provides the means to test a novel treatment for an important brain disease. The opioid epidemic is extensive, ruining an extraordinary number of lives. “This is a moment in history where we need new kinds of treatments, and if this could be of any benefit to patients with opioid use disorder, I would be delighted,” Waszczak explained. Interestingly, just as her initial work with GDNF and Parkinson’s led her to this project, success here could result in many other avenues to explore. Other addictive substances work in a similar to way to opioids in that they stimulate the dopamine reward neurons in the brain; in theory, a similar intranasal GDNF gene therapy could be feasible for reducing relapse with other drugs, such as alcohol, cocaine, amphetamines or nicotine. Waszczak could even go full circle and return to her initial work on Parkinson’s, this time with more data demonstrating the feasibility of an intranasal GDNF gene therapy for brain disorders. She commented on her experience in shifting projects, “in science, a good idea never dies; if it doesn’t succeed one way, you might try and see if there’s another way it can still be beneficial.” For now, she plans on tackling these issues one at a time, but the future for this project is bright with opportunity.

This post was originally published by Corey Ortiz for the Center for Research Innovation.