Gene therapy could mitigate opioid addiction among chronic-pain patients

March 10, 2021

Gene therapy could short-circuit the opioid epidemic.

America's opioid epidemic is rooted in patients' desperation for pain relief, and in a new study, researchers described a potential alternative to the toxic, addictive and dangerous drugs: repressing the body's pain-encoding gene.

The researchers behind the study, published March 10 in Science Translational Medicine, say their gene therapy technology could circumvent the devastating consequences of opioid abuse. In 2018, two-thirds of drug overdoses in the U.S. involved an opioid, 40% of which were prescription-based. 

Opioids are prescribed to treat various levels of pain, ranging from discomfort caused by simple backaches to pain associated with recovery from surgery. But because the drugs are extremely addictive, patients who initially benefit from them can fall down a spiral of abuse, particularly when using them for long-term relief.

"I don't think we'll ever get rid of opioids," said Ana Moreno, the lead author of the study and a postdoctoral researcher from the University of California, San Diego. "I think they're good for surgery or other indications, but for long, chronic use, we need something to replace addictive opioids. They're highly toxic."

Because physicians presently lack a pain relief option as effective as opioids, the drug is often over-prescribed. In 2017, more than 17% of Americans had an opioid prescription filled, with an average dose length of 18 days. And as of 2020, there were over 10 million Americans who misused a prescription opioid within the past year.

In response to the ubiquitous issue, Moreno led a team that studied gene therapy as a pain-relief option that doesn't raise the risk of drug addiction. 

It was considered successful and safe in mice, and the researchers believe it can enter the clinic in one to two years. Moreno and her colleagues even started a company, Navega Therapeutics, to spearhead the translation. The company received some small business grants that contributed to the study's funding.

"We get emails from patients — really often — saying how much they're suffering and what they're going through," Moreno said. "We know that there are definitely a lot of people looking for solutions to chronic pain. Hopefully, we can help them."

Their solution involved going directly to the source of pain. The team tested the possibility of using CRISPR/Cas9 gene manipulation by repressing the human body's gene that encodes the protein channel, which stimulates pain in the first place. The channel is called Nav1.7. 

Moreno discovered Nav1.7's association with pain while studying humans who had a natural mutation to it. She saw that those humans felt no pain whatsoever, and formed the idea of mildly repressing the gene as a form of pain relief.

But Moreno hesitated to use the technology in a traditional way, explaining that her team doesn't want to "permanently mutate chronic pain so someone never feels pain again." For that reason, the researchers decided to use a "dead Cas9 system."

Conventionally, CRISPR/Cas9 is used by sending nucleases, which are like scissors, into a cell nucleus that contains DNA. The nucleases cut the DNA at a point directed by a guide RNA, which acts like a GPS device with a gene entered as the destination. 

Depending on what a researcher sends the nuclease in with, the gene where the strand is snipped gets edited. For example, homology arms can replace an existing gene with a new one. The cell notices a problem because it's been cut, naturally repairs itself and the edited gene remains. 

In contrast, dead Cas9 allows researchers to add regulators, in this case a repression domain, to adjust the expression of a gene without harming it.

"It still has the ability to find a gene of interest with a guide RNA. You can still design the guide to go anywhere you want in the genome," Moreno said. "But, it doesn't cut."

They team tested the dead Cas9 approach in mice. The repression and consequential pain relief was still effective after 44 weeks in mice with inflammatory pain, and after 15 in those with chemotherapy-induced pain. 

"It can still provide really long-lasting relief, but it has less issues in terms of potential side effects," Moreno said. "I would say a couple of years is what we think it will last in humans." 

She added that the method of injection will aid in the treatment's longevity. 

Her team used an adeno-associated virus, or AAV, to put the gene-repression system into mice, and plans to use one for human injections as well. These are not real viruses — they just act like it. They can "infect" a cell and enter it to alter its DNA contents.

"AAVs, in general, can persist for long periods of time, depending on the cell type that you're targeting," Moreno said.

These viruses are the most common platform for gene therapy and are approved by the U.S. Food and Drug Administration. A medication called Luxterna, for instance, has already successfully implemented such a virus in the clinic through gene therapy for eye disease.

The injection, called an intrathecal injection, is not much more invasive than a standard epidural that is also used for pain relief. 

"They actually already do intrathecal injections in humans for steroids," Moreno noted. "It's done in the clinic pretty often."

Because dead Cas9 has yet to be used in humans commercially, the team covered its bases by testing a backup method that predates CRISPR/Cas9 technology. It involved injecting a protein called zinc fingers, which can also recognize DNA targets. The results were consistent.

With regard to cost, Moreno relayed that she hopes to ensure the platform is accessible to all. Due to the widespread discussion of the opioid epidemic, general high demand for alternative therapies and the rise of gene therapies as a whole, she says it's likely to be affordable by the time it reaches the clinic.

"Since we are going after a more common disease, we hope to be able to lower the price so that it is affordable," she said. "Why develop something if no one can pay for it?"

However, Moreno highlighted that some people already pay such high prices for opioids, they could feasibly afford gene therapy, instead. 

"There are patients who are receiving intrathecal pumps administering 40 kilograms of morphine a year," she explained.

A huge first step would be replacing such patients' long-term pain-relief therapies, Moreno said, while her team works toward reducing the price of the gene-editing method to make it accessible for a wider swath of the public as an alternative to lower-priced opioids.

The paper, "Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice," published March 10 in Science Translational Medicine, was authored by Ana M. Moreno, Fernando Alemán, Glaucilene F. Catroli, Matthew Hunt, Michael Hu, Amir Dailamy, Andrew Pla, Sarah A. Woller, Nathan Palmer, Udit Parekh, Daniella McDonald, Vanessa Goodwill, Ian Dryden, Robert F. Hevner, Lauriane Delay, Gilson Gonçalves dos Santos, Tony L. Yaksh and Prashant Mali, University of California, San Diego; and Amanda J. Roberts, Scripps Research Institute.

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