CRISPR-Based Analgesics Aspire to Mitigate Opioid Crisis

Pain is one of the main reasons why people consult a doctor. Often, in the US, they walk away with an opioid prescription. While opioids can calm the nerves and give a temporary state of bliss, they bring adverse side effects and a profound risk of addiction.

Now, a new study in mice shows that CRISPR-based silencing of the gene involved in pain signaling could offer a safer, non-addictive alternative to opioid drugs. If the treatment works in humans, it can give chronic pain patients a safer approach than opioids. The study conducted by Ana Moreno and coworkers was published in Science Translational Medicine.


Source of Pain

A sensation of pain emerges when pain-sensing neurons triggered by stimulus-such as a needle prick or a gut punch-send an electrical signal through the nerves in the spinal cord and upwards to the brain. This happens when a set of channel proteins lined on the membrane of pain-sensing neurons open and close to allow ions to pass through, which generates and transmits a current along the nerve. Normally, the pain signaling stops after the source of pain resolves, but sometimes the signaling persists even after that, resulting in chronic pain.

There are many channels that operate simultaneously to relay a neuronal signal. One channel, called Nav1.7, however, stands out for the remarkable pain disorders that arise when it malfunctions. The relevance of this channel can be seen in humans with overactive or underactive Nav1.7 channel-people with overactive channels are prone to attacks of burning sensation, and those with underactive channels feel no pain at all.

Based on this observation, the Nav1.7 channel has been targeted by multiple methods to reduce pain. Some have used small molecule inhibitors to stop the function of the channel, while others developed antibodies that can block the channel in a particular confirmation. However, none of these efforts have so far resulted in an approved therapy for chronic pain, mainly due to the non-specificity of small molecule inhibitors and reduced potency of antibody-based drugs. 


The New CRISPR Study

To overcome these challenges, Ana Moreno and her colleagues decided to reversibly stop the gene for Nav1.7 channel from producing the protein. They used a modified version of the Cas9 protein that can target the gene sequence but not cut it. This is unlike other CRISPR-Cas9 editing tools, which utilize Cas9’s DNA nicking power to repair mutated genes.

By using modified Cas9, the group prevented Nav1.7 protein from being made. The researchers enhanced this silencing effect by attaching Cas9 to a repressor that further inhibited the expression of the channel gene. The modified gene-editing machinery was then packed in the AAV vector and injected into the spinal cord of mice. The group named this epigenetic strategy as LATER short for long-lasting analgesia via targeted in vivo epigenetic repression of Nav1.7.

To understand the effect of the CRISPR therapy on pain relief, the group induced chronic pain in mice by injecting pain-inducing agents such as chemotherapy drug, paclitaxel, and measured the pain response of drug-injected mice with and without the CRISPR machinery. While paclitaxel-induced severe pain, injection of the gene-silencing treatment numbed it.

Approximately 1 month after the injection, mice with CRISPR therapy felt no pain, but control mice remained hypersensitive. This approach also prevented the pain in mice before they were given injections of either inflammation-causing compound carrageenan or a molecule called BzATP that increase pain sensitivity. 

Interestingly, the CRISPR-treated mice were not completely insensitive to pain. 

When the paws of treated and untreated mice were touched with a hot surface, they felt the pain. This shows that the treatment doesn’t create a dangerous situation where the body is unable to sense any pain. 

While it is not clear how long the effects of the therapy last, the group reported that they could see pain-numbing effects for as long as 44 weeks. Importantly, the treatment is very specific to Nav1.7 channels and prevents suppression of other Nav channels. This is in contrast to non-specific effects seen for small molecule inhibitors of Nav1.7.  

All in all, by temporarily stopping the production of the channel protein, the group could increase the animal’s pain tolerance; lower the pain sensitivity, and provide months of pain relief without causing numbness. 


Commercialization of the Technology

The pain medication industry is rapidly growing. More than $560 billion are spent annually on healthcare due to pain disorders. A concurrent rise has been seen in opioid prescriptions. As a result, opioid addiction and overdose have become a grave problem.

Ana Moreno and her team of collaborators are trying to solve this problem. She and her collaborators have found a company called Navega Therapeutics that is working towards tackling the opioid epidemic using novel gene therapy. Moreno hopes that the approach published in their latest study will help treat common types of chronic pain. 

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