Could CRISPR Gene-Editing Technology Be an Answer to Chronic Pain?
Posted on by Dr. Francis Collins
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
The research sounds very promising and I hope it is the start of helping many patients who suffer, but your statement at the end about opioids being the cause of the overdose crisis was misleading. Prescribed opioid pain medication is not the cause of the current overdose crisis. Illicit fentanyl is. Because they are both listed as opioids is the issue. Less than 2% of patients who take pain medication will become addicted. If they were as addictive as articles like this suggest, there would be a whole world of addicts. There are millions of patients suffering excruciating pain, whose productive lives have suddenly stopped because doctors stopped prescribing what was helping them function. If taken as prescribed, opioid pain medication has worked for many years allowing people to have functional and productive lives. The CDC guidelines used flawed studies and DEA has terrorized doctors into stopping prescribing pain medications at all. After 10 failed spinal surgeries, scoliosis, degenerative disk disease, arthritis and sciatica, I tried every alternative treatment available, before trying narcotic pain pills. It allowed me to be a functional member of society again. Now I am bedridden with pain you cannot imagine a human could survive. All because my doctor was forced to stop prescribing the opioid medication that I took for 31 years with no addiction issues, that allowed me to live normally. He said he couldn’t take the chance anymore on losing his medical license by continuing to prescribe opioid pain medication. Many, many people are committing suicide every day due to their unrelenting pain after their doctors just stopped prescribing or left their practice altogether. Veterans, cancer and major surgical patients are being offered only Tylenol now. It is patient genocide that not many are aware of yet. Absolutely help people struggling with addiction, but until treatments like this, if proven successful, are available, stop blaming the opioid crisis on pain medication that has helped millions of patients like me.
Jeanette, Thank You for so exquisitely expressing the difference between an opioid abuser and a pain patient taking opioid pain medication, the only thing that alleviates pain for a person suffering from chronic pain and the stigma put on patients that have only this one option to be a functioning member of society.
I’ve been Suffering a chronic pain For 15 years Can’t sleep in my bed for 15 years I’m in a chair So when I’m home it is 24 7 Starting with the pain My legs And feet Feel like I’m plugged into a wall socket I had those attacks6-8 hours At Evening hours Where’s my down Sometimes by morning my Pain Will ease up By that time I’m too weak To do much the next day Because I try To shake Off Pain I’m going through Stomping my feet shaking my body my neck my arms praying for it to stop now I have burning in my fingers and hands that feels like I put my fingers on a stove top and burn myself that keeps me from sleeping. I wake up my neck is in serious pain from dropping because I’m in my chair.when I take my Norco I can rest and the next day get out of my chair and do things I’m tired of doctors prescribing zombie meds that only make me feel tired and drowsy I know what works for me recently I have been in the hospital diagnosed with sepsis and stage three kidney failure and heart failure I’m still taking Norco as needed and more meds properly and don’t abuse them for ten years now trying to get my strength back still in my chair my legs hurt to my to recline so my feet are still on the floor it really hurts and I sure miss lying down I feel sorry for others that suffer with pain I hope one day we can be free from pain while we are above ground not under
I agree with Jeanette. I have had a similar history with regards to failed back surgeries, chronic pain for many years that has totally destroyed my life. So far, they have fortunately not taken my pain patches away and I honestly cannot imagine how I could continue with the type of pain I am constantly in. The pain meds are a lifesaver, though they do not take away all pain, but still, cannot imagine what she and others have gone through when their meds have been taken away. I delayed starting pain meds as long as I possibly could and do not like meds in general but anybody that believes it is a choice and anyone that takes them are addicts, are completely clueless. It makes me angry that people that already suffer an unimaginable existence already (and I should and do understand this very well), should have to be made to suffer even more needlessly. People that live “normal” lives cannot possibly comprehend this type of hell. Please develop medications, gene therapies and other therapies that work. Also, am doing PRP for my back which is not covered by insurance but does seem to be helping. Would be nice to see these therapies covered by insurance and more controlled clinical studies conducted.
any update on crispr for pain control
Jeanette, I am deeply sorry for your pain. I agree with you about people contemplating suicide. I have think about it myself and wonder how I can do it if my pain gets any higher.
Promising….. But the last paragraph has some false info in it.
For the upcoming clinic, are you going to implement the same informed consent protocols that you used for the sickle cell patients? Informed consent is very important to have from the patients at these clinics and I think that what you guys did to improve the informed consent with the sickle cell patients trials was a step in the right direction. If you are going to implement those same protocols, would there be any additions to what was done before? . . .
Great article! Gene editing could be the required opioid-free solution for chronic pain. The botulinum toxin is also another alternative. What is concerning is how many people can access these treatments which are expensive, whereas chronic pain is such a common ailment.
thanks for sharing this amazing post. What is concerning is how many people can access these treatments, which are expensive, whereas chronic pain is such a common ailment . . .
Thank you for sharing this article, I read your blog and found some very important information on pain management and it’s very helpful me.
can you please give us an update?
any update on crispr for pain….please….thank you
any hope for crispr to help psc colangitis and which hospital or university is best for psc…..my niece is only 39 and has it……thank you