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Could CRISPR Gene-Editing Technology Be an Answer to Chronic Pain?

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Gene editing has shown great promise as a non-heritable way to treat a wide range of conditions, including many genetic diseases and more recently, even COVID-19. But could a version of the CRISPR gene-editing tool also help deliver long-lasting pain relief without the risk of addiction associated with prescription opioid drugs?

In work recently published in the journal Science Translational Medicine, researchers demonstrated in mice that a modified version of the CRISPR system can be used to “turn off” a gene in critical neurons to block the transmission of pain signals [1]. While much more study is needed and the approach is still far from being tested in people, the findings suggest that this new CRISPR-based strategy could form the basis for a whole new way to manage chronic pain.

This novel approach to treating chronic pain occurred to Ana Moreno, the study’s first author, when she was a Ph.D. student in the NIH-supported lab of Prashant Mali, University of California, San Diego. Mali had been studying a wide range of novel gene- and cell-based therapeutics. While reading up on both, Moreno landed on a paper about a mutation in a gene that encodes a pain-enhancing protein in spinal neurons called NaV1.7.

Moreno read that kids born with a loss-of-function mutation in this gene have a rare condition known as congenital insensitivity to pain (CIP). They literally don’t sense and respond to pain. Although these children often fail to recognize serious injuries because of the absence of pain to alert them, they have no other noticeable physical effects of the condition.

For Moreno, something clicked. What if it were possible to engineer a new kind of treatment—one designed to turn this gene down or fully off and stop people from feeling chronic pain?

Moreno also had an idea about how to do it. She’d been working on repressing or “turning off” genes using a version of CRISPR known as “dead” Cas9 [2]. In CRISPR systems designed to edit DNA, the Cas9 enzyme is often likened to a pair of scissors. Its job is to cut DNA in just the right spot with the help of an RNA guide. However, CRISPR-dead Cas9 no longer has any ability to cut DNA. It simply sticks to its gene target and blocks its expression. Another advantage is that the system won’t lead to any permanent DNA changes, since any treatment based on CRISPR-dead Cas9 might be safely reversed.

After establishing that the technique worked in cells, Moreno and colleagues moved to studies of laboratory mice. They injected viral vectors carrying the CRISPR treatment into mice with different types of chronic pain, including inflammatory and chemotherapy-induced pain.

Moreno and colleagues determined that all the mice showed evidence of durable pain relief. Remarkably, the treatment also lasted for three months or more and, importantly, without any signs of side effects. The researchers are also exploring another approach to do the same thing using a different set of editing tools called zinc finger nucleases (ZFNs).

The researchers say that one of these approaches might one day work for people with a large number of chronic pain conditions that involve transmission of the pain signal through NaV1.7. That includes diabetic polyneuropathy, sciatica, and osteoarthritis. It also could provide relief for patients undergoing chemotherapy, along with those suffering from many other conditions. Moreno and Mali have co-founded the spinoff company Navega Therapeutics, San Diego, CA, to work on the preclinical steps necessary to help move their approach closer to the clinic.

Chronic pain is a devastating public health problem. While opioids are effective for acute pain, they can do more harm than good for many chronic pain conditions, and they are responsible for a nationwide crisis of addiction and drug overdose deaths [3]. We cannot solve any of these problems without finding new ways to treat chronic pain. As we look to the future, it’s hopeful that innovative new therapeutics such as this gene-editing system could one day help to bring much needed relief.

References:

[1] Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice. Moreno AM, Alemán F, Catroli GF, Hunt M, Hu M, Dailamy A, Pla A, Woller SA, Palmer N, Parekh U, McDonald D, Roberts AJ, Goodwill V, Dryden I, Hevner RF, Delay L, Gonçalves Dos Santos G, Yaksh TL, Mali P. Sci Transl Med. 2021 Mar 10;13(584):eaay9056.

[2] Nuclease dead Cas9 is a programmable roadblock for DNA replication. Whinn KS, Kaur G, Lewis JS, Schauer GD, Mueller SH, Jergic S, Maynard H, Gan ZY, Naganbabu M, Bruchez MP, O’Donnell ME, Dixon NE, van Oijen AM, Ghodke H. Sci Rep. 2019 Sep 16;9(1):13292.

[3] Drug Overdose Deaths. Centers for Disease Control and Prevention.

Links:

Congenital insensitivity to pain (National Center for Advancing Translational Sciences/NIH)

Opioids (National Institute on Drug Abuse/NIH)

Mali Lab (University of California, San Diego)

Navega Therapeutics (San Diego, CA)

NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke

29 Comments

  • Kwadwo Dakwa says:

    As a physician for treatment of chronic non malignant pain, l am very interested to know if this actually help treat my patients when it’s adequately studied.

  • Conrad Clyburn says:

    Dr. Moreno, Congratulations on the continued progress being advanced by Navega and the recent recognition as a 2020 Mitchell Max Awardee. Please continue this important work.

  • Rj L. says:

    I had a mechanical failure in a bicycle race and crashed. My lower back has been in pain since then.
    How do I go about getting an appointment with you?

  • janet a. says:

    If you have clinical trials with people sometime, I would like to be a part of that. I wish I could get rid of my chronic pain.

  • Chris G. says:

    I believe, sign me up.

  • Loretta B. says:

    I would be very interested in taking part in the human trials. It has been 8 years since I had a stroke and have been struggling with post stroke pain ever since. One pain clinic wouldn’t even see me because my medical doctor prescribed the medication(s) that may help and the pain clinic reviewed the medication I had tried and told me they couldn’t help any further either. They directed me to the university hospital pain clinic!

  • kalpana K Patel says:

    Congratulations to Dr. Moreno and Dr. Mali for the new innovating field! Great idea and hope Gene editing will bring the relief in future from pain and Navega will bring new therapies soon.

  • Kikirae says:

    I have Lyme Disease, Fibromyalgia, and now breast cancer. I do not respond to opioids or most pain meds. I would be willing to do anything to relieve the constant pain. I wouldn’t care if it killed me. I just can’t live like this any longer …

  • Laurie H. says:

    I injured my back when I was 23. I literally have not been able to sit for over 10 minutes w/out being in excruciating pain since then. I’m now 62. In 02 I had back fusion surgery on my Si joint which was unsuccessful. I’ve had approx. 12 Radiofrequency treatments which are extremely painful. I just had an Epidural which has helped but it’s bad on my bones. I’m seriously thinking about having the back machine (I forgot what it’s called) surgically placed in my back next. Please let me know when you’ve tested this on people and the outcome. I’m extremely interested in having this done to eliminate my back pain. Thanks!!!

  • Mary says:

    As a person dealing with chronic pain for over 7 years, i am interested in knowing more, would this actually help someone like me not to feel the effects of chronic pain and what would be the side effects?

  • Neil Donovan says:

    There are a few unfortunate people who experience a shingles outbreak in their eyes. A friend of mine was heavily medicated with pain meds. He died.

  • STEVEN W. says:

    If you are looking for chronic pain patients to try, I’m available . . . Been in horrible pain for years.

  • Diana P. says:

    I live on a spinal cord stimulator. January and February I had unexplainable nerve pain all over my body. For the first time even the nerves in my teeth hurt. I paced all night, it hurt tremendously to lie down. ER, 3x, rapid Covid test, when I could barely walk. Morphine, Toradol, Diluadid, Famotine, nothing worked. Blocks, Prednisone, FINALLY after almost 2 months, I asked for Valium. That did it.
    2 months that I prayed to die. No sleep of course. I’ve suffered this from a infected MESH from a hernia almost 19 years ago. 19 surgeries later, I’ve had many, many, “setbacks,” but nothing like this.
    Please, I am NOT sick. I was healthy, worked out, had a career, and overnight my life changed. Please
    I beg you, if you could help me, I would be forever grateful. Tell me what to do and I WILL DO IT. My diet is clean. I do walk whenever I can, due to the facts that I miss working out, which was a daily habit.
    Any insight I would welcome greatly. I am fully vaccinated. Checked my antibodies. Thank God all good on that issue. Again, . . . any information, I would be very grateful.

  • Pamela C. says:

    I am a chronic pain patient with multiple conditions and would do anything that does not involve cutting into my body or implant. I am very upset that opioids have become a political issue and that people like me, with chronic pain conditions who have never abused opioids, are now being prescribed by government instead of doctors. This is insanity. Addicts will always find a way and I greatly resent being put in the same category as the people who use use drugs recreationally. Why should I suffer because a senator’s son or daughter cannot control themselves?

  • Gerilyn C. says:

    After Septic shock, I suffer from unbearable cramps presumably from nerve aftereffects. Would love to participate in a study.

  • Michael J N. says:

    I am interested in being a participant in a human study of this, I have been living with chronic pain for nine years due to Post-laminectomy syndrome on L4 and Spondylosis in C 4,5,6 anything that could help me with this would be a great help with my daily fight with pain.

  • Ron says:

    Wow! Sounds like a better option than all of the failed procedures I’ve been reading about. I’ve lived with scoliosis all my 70+ years, however about 22 years ago I was in car accident that severely ruptured L disks, 3,4 & 5. Shortly thereafter my left hip developed a cyst in the joint because of dysplasia. My right knee is arthritic so now I am in pain with nearly every move I make. Walking has also become painful. I’ve been active & athletic for over half my life, but now even swimming is out of the question. I do have shoe adjustments that help my right leg length discrepancy (about 1.5 inches) but that gets tricky when I decide to changes shoes or they wear down. I don’t use opioids, but I do alternate between Tylenol, Advil and Aleve daily. I get minimal relief. I don’t have confidence in recovering from multiple surgeries because rehab would require added pressure on those anatomic areas that are already compromised. I am on the edge of desperation because moving about and sometimes sleeping is never pain-free. Please let me know where I can sign up. I already got my two COVID shots, so volunteering for something like this would probably be less worrisome.

  • Cheryl O. says:

    I’m intrigued by the promise of this treatment. I suffer from debilitating spinal nerve pain due to ruptured discs (Cervical & Lumbar), degenerative disc disease, Scoliosis, etc. I do not seek a surgical solution because it is so often not successful. But I want to live my life and be able to serve others in relative freedom from pain. I pray that the CRISPR technology will soon be available to those willing to try it. I am!!

  • renee t. says:

    Sounds good……is it ready for humans yet? I need it, thank you

  • John S says:

    I’m like the other comments, suffering in horrific daily pain desperately willing to try anything that would help . . .Thanks for all your hard dedicated work you guys have done. Rods/screws/fusions in back, neck and degenerating spine at age 60. In perfect health otherwise…

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