Using CRISPR to switch off pain gene becomes a possibility with new study
A path-breaking study reports success in disabling an important gene that
is responsible for inducing the sensation of pain. This discovery could
be of invaluable assistance to millions of patients with chronic pain,
helping them to manage their condition better and live with a vastly
better quality of life.
The tool used to alter the DNA is the powerful CRISPR editor. This has already proved its worth in a host of laboratory gene-editing procedures, but clinically, its use has largely been restricted to rare inherited medical conditions.
For instance, last month, a patient suffering from sickle cell anemia due to the production of abnormal hemoglobin because of a gene defect was successfully reverted to having normal hemoglobin using this method.
CRISPR functions by means of homing molecules that identify and zoom in on a designated or target gene to be edited. Once identified, the target gene is removed neatly, the normal copy is inserted, and the cut ends spliced with the inserted sequence. In effect, a find-and-replace routine has been used.
To achieve this, they used CRISPR to edit molecules attached to the basic DNA strand, called epigenetic molecules. These molecules are not part of the genetic information in the DNA but have an immense influence on the way the genes are expressed.
This is called epigenome editing and does not carry the same risk of permanently altering the genetic blueprint of the individual. The advantage is that the target gene can be prevented from being activated, or can be activated, according to need, while still remaining intact.
The researchers then focused on using this to treat pain without the risks and adverse effects of opioid medication. They tried to edit the epigenetic marker that activated this pathway using CRISPR inserted into a viral vector. The virus used is a harmless one.
These treated viral particles were inserted into the spine so that they can enter the nerve cells there. The scientists hoped that once inside the cell, the virus would release the CRISPR tool as it disassembled itself in preparation for replication. The gene editor would then, presumably, carry out its task of editing the epigenetic marker that activates the SCN9A gene.
Though the researchers found that they could not completely silence the pain because not all nerve cells were penetrated by the viral vector, there was a significant reduction.
Moreover, the degree of pain reduction was tunable, as with conventional pain medication. The more virus they injected, the greater was the pain relief, but it lasted much, much longer than with a painkiller.
The big benefit of the current therapy is that unlike current approaches that focus on relieving pain by administering opioid-based medication, it doesn’t carry the risk of addiction. At present, the US is facing an unprecedented two million-strong caseload of opioid addiction due to improper and over-zealous prescription of opioids for the treatment of pain.
Moreno cites the case of cancer patients who are unable to tolerate chemotherapy because of the intense associated pain, even though they know it could save their lives. The paradox with chemotherapy for cancer is that higher doses of these cytotoxic drugs increase the chances of surviving cancer-free for a longer time – but may leave the survivor with chronic pain.
In many centers, therefore, patients on chemotherapy are given morphine to dull their pain. This may, however, leave them unable to function normally because of the associated somnolence and tiredness.
On the other hand, the effect is reversible, which is important in allowing people treated in this way to feel pain normally once their need for dulled pain is no longer present, such as following the termination of chemotherapy.
The other side of the discovery was also raised by Urnov: what if people used it to produce humans who could no longer feel pain and could, therefore, fight to the death without fear? In the current world scenario, such a terrifying possibility also needs to be considered for this exciting new discovery– a point not missed by Russian President Vladimir Putin.
The tool - CRISPR
The gene therapy was brought out by scientists from a California startup called Navega Therapeutics. The basis of this technique is gene therapy, making planned and selective alterations in the patient’s DNA to repress the expression of a gene that is responsible for sending the pain signals up the nervous network in the spine.The tool used to alter the DNA is the powerful CRISPR editor. This has already proved its worth in a host of laboratory gene-editing procedures, but clinically, its use has largely been restricted to rare inherited medical conditions.
For instance, last month, a patient suffering from sickle cell anemia due to the production of abnormal hemoglobin because of a gene defect was successfully reverted to having normal hemoglobin using this method.
CRISPR functions by means of homing molecules that identify and zoom in on a designated or target gene to be edited. Once identified, the target gene is removed neatly, the normal copy is inserted, and the cut ends spliced with the inserted sequence. In effect, a find-and-replace routine has been used.
The study
In the current study, the scientists were able to avoid the potential dangers of cutting out a gene altogether, which include inadvertently removing or interfering with normal neighboring regulatory or coding DNA. This could affect many functions in the body. Instead, they concentrated on regulating the expression of the gene of interest rather than removing it.To achieve this, they used CRISPR to edit molecules attached to the basic DNA strand, called epigenetic molecules. These molecules are not part of the genetic information in the DNA but have an immense influence on the way the genes are expressed.
This is called epigenome editing and does not carry the same risk of permanently altering the genetic blueprint of the individual. The advantage is that the target gene can be prevented from being activated, or can be activated, according to need, while still remaining intact.
The target
The gene is called SCN9A. It was back in 2006 that certain mutations in this gene were found to deprive the affected individual of the ability to feel pain. This was because the mutated gene down-regulated the passage of the pain signals across the neural pathway, by controlling certain molecules involved in this process, found on the cell surface of the neurons.The researchers then focused on using this to treat pain without the risks and adverse effects of opioid medication. They tried to edit the epigenetic marker that activated this pathway using CRISPR inserted into a viral vector. The virus used is a harmless one.
These treated viral particles were inserted into the spine so that they can enter the nerve cells there. The scientists hoped that once inside the cell, the virus would release the CRISPR tool as it disassembled itself in preparation for replication. The gene editor would then, presumably, carry out its task of editing the epigenetic marker that activates the SCN9A gene.
The results
The first round of testing of the therapy on mice has successfully concluded, says Moreno. “We are really excited because we have seen, in three different pain models, a decrease in overall pain.”Though the researchers found that they could not completely silence the pain because not all nerve cells were penetrated by the viral vector, there was a significant reduction.
Moreover, the degree of pain reduction was tunable, as with conventional pain medication. The more virus they injected, the greater was the pain relief, but it lasted much, much longer than with a painkiller.
The big benefit of the current therapy is that unlike current approaches that focus on relieving pain by administering opioid-based medication, it doesn’t carry the risk of addiction. At present, the US is facing an unprecedented two million-strong caseload of opioid addiction due to improper and over-zealous prescription of opioids for the treatment of pain.
Moreno cites the case of cancer patients who are unable to tolerate chemotherapy because of the intense associated pain, even though they know it could save their lives. The paradox with chemotherapy for cancer is that higher doses of these cytotoxic drugs increase the chances of surviving cancer-free for a longer time – but may leave the survivor with chronic pain.
In many centers, therefore, patients on chemotherapy are given morphine to dull their pain. This may, however, leave them unable to function normally because of the associated somnolence and tiredness.
On the other hand, the effect is reversible, which is important in allowing people treated in this way to feel pain normally once their need for dulled pain is no longer present, such as following the termination of chemotherapy.
The future
The American scientists now want to begin testing it in human patients from the next year. If it is proved to be medically safe and clinically effective, these researchers could have helped to bring about a dramatic reduction in suffering for a vast army of people with terminal painful illnesses and with chronic pain. However, the earliest date at which approval is envisaged is five years from now.The other side of the discovery was also raised by Urnov: what if people used it to produce humans who could no longer feel pain and could, therefore, fight to the death without fear? In the current world scenario, such a terrifying possibility also needs to be considered for this exciting new discovery– a point not missed by Russian President Vladimir Putin.