Opioid use disorder kills tens of thousands of Americans a year, upends the lives of many more and is notoriously difficult to treat.

Could help come in the form of a nasal spray that delivers a novel gene therapy?

Northeastern pharmaceutical sciences professor Barbara L. Waszczak says preliminary research shows the approach may stop drug cravings that lead to relapse and end up saving lives.

Waszczak and collaborators recently received the second installment of a nearly $7 million grant from the National Institute on Drug Abuse to develop a treatment that would use an intranasal route to transport nanoparticle therapy directly to the brain to restore dopamine transmitters.

Dopamine neurons play a role in experiencing and remembering pleasure, making it an important part of the brain’s reward circuitry, says Waszczak, a principal investigator in the study.

But when dopamine is released frequently due to chronic drug use, the neurons get overtaxed, she says.

“After you have got to the point where you are addicted, you have depleted the dopamine stores in your brain in this reward circuit,” Waszczak says.

“There’s not enough left to sustain normal function. You feel terrible. You can’t experience pleasure.  You continue to feel intense craving for the drug.”

“Our treatment is to try and get the dopamine cells to recover so people have enough dopamine to sustain normal function by reducing cravings and the risk of relapse,” Waszczak says.

“It would basically reset the reward system so it’s normal again.”

Waszczak says Northeastern University and Copernicus Therapeutics Inc. hold a joint patent on technology she developed that would use an intranasal route to deliver the therapeutic treatment directly to the brain.

The treatment process involves compressing plasmid DNA segments that encode a protein known as GDNF into nanoparticles, Waszczak says.

Scientists have shown that GDNF, short for glial cell derived neurotrophic factor, plays a role in promoting the survival and recovery of dopamine neurons.

The problem was how to get it into the brain, Waszczak says.

Trying to deliver the nanoparticles by IV therapy doesn’t work because barely any of them make it across the blood/brain barrier, she says. 

“Intranasal delivery bypasses this problem,” Waszczak says, calling it a “novel route of administration.”

“No one has attempted to treat opioid use disorder or any addictive disorder with this strategy,” Waszczak says.

She says Elizabeth M. Byrnes, a co-principal investigator from the Tufts University Cummings School of Veterinary Medicine, has cleared the “first hurdle” in the research by demonstrating that the gene therapy reduced opioid cravings in rats hooked on self-administered doses of IV oxycodone.

After being forced into abstinence, the rats were divided into groups that received either the GDNF nasal spray or a saline spray. Rats that had received the gene therapy were less likely to push levers to try and dose themselves again, Waszczak says.

In this second year of the phase one portion of the federal grant, researcher Emmanuel Pothos, a co-principal investigator at the Tufts University School of Medicine is continuing to study rat brains to see “whether or not they are releasing more dopamine after they get the intranasal GDNF treatment,” Waszczak says.

In addition, researchers at a contract lab are in the middle of a study in monkeys to see if GDNF levels are higher in non-human primate brains after they received the gene therapy versus the saline nasal spray, she says.

Positive results would be a “milestone for the next phase of grant approval and signal it could work in humans,” Waszczak says.

If the current phase of the research is successful, the study is eligible to receive about $8 million in additional federal funding to prepare the groundwork for an investigational new drug application for human clinical trials, Waszczak says.

 As the prime principal investigator on the grant, the funding would go to Northeastern  to allocate to the Tufts co-principal investigators and Copernicus collaborators.

The stakes are high, Waszczak says.

The NIDA says deaths from all types of opioids continue to climb dramatically, going from 21,089 in 2010 to 68,630 in 2020 and 80,411 in 2021.

While various treatments exist, none have been able to prevent the extremely high rate of relapse experienced by many users giving up opioids.

“You basically lose your natural sense of pleasure and reward,” Waszczak says.

The nanoparticle therapy is different than the over-the-counter nasal spray approved by the US Food and Drug Administration on Wednesday. That spray, given during an overdose, delivers the life-saving opioid antidote Narcan.

 Going on opioid antagonists such as Vivitrol can block users from experiencing an opioid high, but it does not stop their craving for opioids or restore the normal sense of pleasure in everyday activities, she says.

The length of time it takes to naturally restore dopamine levels in the brain is a likely cause of frequent relapses, which is why a lot is riding on expectations that the novel gene therapy approach could ramp up the process, Waszczak says.

 She says the intranasal approach allows the nanoparticles, which are produced by Copernicus, to go from nasal passages directly into fluid-filled spaces between cells in brain tissue. From there, the nanoparticles gain entry into cells and increase their production of GDNF.

Dr. Mark J. Cooper, senior vice president of science and medical affairs at Copernicus, said in a press release that data from the study could also serve as a “template for exploring gene therapy approaches for other substance use disorders.”

“We … believe this is a critical proof point toward moving our patented nanoparticle platform forward into human trials for opioid use disorder as well as other indications in the brain, eye and lung.”

Waszczak says that she first got involved with intranasal delivery of gene therapy as a possible treatment for Parkinson’s disease. 

“All of these potential uses are in the patent” jointly held with Copernicus, she says.

In the meantime, the researchers are looking for investors interested in licensing the patent and helping to bring the invention to market, Waszczak says. 

If the novel gene therapy holds up, it could make a huge difference in the lives of opioid users, she says. “We might help them to permanently let go of the addictive behavior.”

Cynthia McCormick Hibbert is a Northeastern Global News reporter. Email her at c.hibbert@northeastern.edu or contact her on Twitter @HibbertCynthia.