Ana Moreno, PhD '19
Founder and CEO, Navega Therapuetics, IncEmbedded Files
With Gene Therapy, Scientists Develop Opioid-Free Solution for Chronic Pain
With Gene Therapy, Scientists Develop Opioid-Free Solution for Chronic Pain
Gene therapy for chronic pain could offer a safer, non-addictive alternative to opioids
Gene therapy for chronic pain could offer a safer, non-addictive alternative to opioids
Ana Morena, a bioengineering alumna from Prof. Prashant Mali’s laboratory, and her collaborators have developed a new therapy, which temporarily represses a gene involved in sensing pain. It increased pain tolerance in mice, lowered their sensitivity to pain and provided months of pain relief without causing numbness.
The researchers reported their findings in a paper published Mar. 10 in Science Translational Medicine and the work was highlighted by Francis Collins in the NIH Director’s Blog.
The gene therapy could be used to treat a broad range of chronic pain conditions, from lower back pain to rare neuropathic pain disorders—conditions for which opioid painkillers are the current standard of care.
“What we have right now does not work,” said first author Ana Moreno, a bioengineering alumna from the UC San Diego Jacobs School of Engineering. Opioids can make people more sensitive to pain over time, leading them to rely on increasingly higher doses. “There’s a desperate need for a treatment that’s effective, long-lasting and non-addictive.”
The idea for such a treatment emerged when Moreno was a Ph.D. student in Professor Prashant Mali’s lab. Mali had been investigating the possibility of applying CRISPR-based gene therapy approaches to rare as well as common human diseases. Moreno’s project focused on exploring potential therapeutic avenues. One day, she came across a paper about a genetic mutation that causes humans to feel no pain. This mutation inactivates a protein in pain-transmitting neurons in the spinal cord, called NaV1.7. In individuals lacking functional NaV1.7, sensations like touching something hot or sharp do not register as pain. On the other hand, a gene mutation that leads to overexpression of NaV1.7 causes individuals to feel more pain.
When Moreno read this, it clicked. “By targeting this gene, we could alter the pain phenotype,” she said. “What’s also cool is that this gene is only involved in pain. There aren’t any severe side effects observed with this mutation.”
Non-Permanent Gene Therapy
Non-Permanent Gene Therapy
Moreno had been working on gene repression using the CRISPR gene editing tool as part of her dissertation. Specifically, she was working with a version of CRISPR that uses what’s called “dead” Cas9, which lacks the ability to cut DNA. Instead, it sticks to a gene target and blocks its expression.
Moreno saw an opportunity to use this approach to repress the gene that codes for NaV1.7. She points out an appeal of this approach: “It’s not cutting out any genes, so there are no permanent changes to the genome. You wouldn’t want to permanently lose the ability to feel pain,” she said. “One of the biggest concerns with CRISPR gene editing is off-target effects. Once you cut DNA, that’s it. You can’t go back. With dead Cas9, we’re not doing something irreversible.”
Prashant Mali, PhD
Associate Professor of Bioengineering
Fig. 1 Schematic of the overall strategy used for in situ NaV1.7 repression using ZFP-KRAB and KRAB-dCas9 via the intrathecal route of administration (ROA).
NaV1.7 is a DRG channel involved in the transduction of noxious stimuli into electric impulses at the peripheral terminals of DRG neurons. In situ repression of NaV1.7 via AAV-ZFP-KRAB and AAV-KRAB-dCas9 is achieved through intrathecal injection, leading to disruption of the pain signal before reaching the brain.
NaV1.7 is a DRG channel involved in the transduction of noxious stimuli into electric impulses at the peripheral terminals of DRG neurons. In situ repression of NaV1.7 via AAV-ZFP-KRAB and AAV-KRAB-dCas9 is achieved through intrathecal injection, leading to disruption of the pain signal before reaching the brain.
Mali, who is a co-senior author of the study, says that this use of dead Cas9 opens the door to using gene therapy to target common diseases and chronic ailments.
“In some common diseases, the issue is that a gene is being misexpressed. You don’t want to completely shut it down,” he said. “But if you could turn down the dose of that gene, you could bring it to a level where it is not pathogenic. That is what we are doing here. We don’t completely take away the pain phenotype, we dampen it.”
Moreno and Mali have co-founded a spinoff company Navega Therapeutics to work on translating this gene therapy approach, which they developed at UC San Diego, into the clinic. They teamed up with Tony Yaksh, an expert in pain systems and a professor of anesthesiology and pharmacology at UC San Diego School of Medicine. Yaksh is a scientific advisor to Navega and co-senior author of the study.
Paper title: “Long-lasting Analgesia via Targeted in situ Repression of NaV1.7.” Co-authors include Fernando Alemán, Glaucilene F. Catroli, Matthew Hunt, Michael Hu, Amir Dailamy, Andrew Pla, Sarah A. Woller, Nathan Palmer, Udit Parekh, Daniella McDonald, Amanda J. Robers, Vanessa Goodwill, Ian Dryden, Robert F. Hevner, Lauriane Delay and Gilson Gonçalves dos Santos.
This work was supported by UC San Diego Institutional Funds and the National Institutes of Health (grants R01HG009285, RO1CA222826, RO1GM123313, R43CA239940, R43NS112088, R01NS102432, R01NS099338).
Disclosure: Ana Moreno, Fernando Alemán, Prashant Mali and Tony Yaksh have a financial interest in Navega Therapeutics. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.
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