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Challenges & Successes in Human CRISPR Trials

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A recent op-ed in the New York Times asked why scientists and clinicians aren't using CRISPR to treat more human diseases. It outlined the possibilities, the success stories, and some of the reasons why this technology is not applied more often. It also raised important points about the desperation some people have because of genetic diseases that are going to end their lives or the lives of their children. Trials of new drugs and medical devices take a long time and a lot of money, which can often come from investors who are trying to profit from something that is medically necessary for a small number of people. They also require a major investment from patients, who are taking a big risk. I personally agree with the opinion that we should do more to bring genetic engineering to the clinic and make it more affordable and easier to apply quickly to people who are facing a death sentence from their genetic disease.

However, the op-ed did not discuss some of the plain truths about medicine - not every experiment has been successful, some people are mistrustful of advances in medicine, and we have to ensure that people are not put in danger by new technologies. While CRISPR has been a tremendous advance for research and could be life-saving for many people, we cannot yet guarantee that it is safe for everyone to use, and there is no way to know who might suffer an adverse event. One issue with using CRISPR is that is typically has to be delivered to the right cells, and into the nucleus where the genome is. This means that viral vectors are typically used as a delivery system, and they can pose their own risks. CRISPR can also make unintended, off-target edits to the genome in some cases, though there are ways to minimize the chances that will happen.

CRISPR has already been used to treat several different genetic disorders, with varying degrees of success. Two individuals, one with transfusion-dependent β-thalassemia (TDT) and the other with SCD, received CRISPR therapeutics tailored to their condition, and in 2021 - over a year after the treatment, both patients were still producing healthy cells because of their therapy, and the symptoms of their diseases had been relieved. But in a test of a CRISPR-based treatment for Leber congenital amaurosis, only three of 14 patients had “clinically meaningful” improvements to their vision.

There is other good news, though. Ten young children who have a variation of a disorder known as 'bubble boy disease,' Artemis-SCID (severe combined immunodeficiency disorder), were recently treated successfully with gene therapy.


CRISPR still has the potential to treat a huge number of human diseases, and options are being explored. There are trials for other CRISPR-based therapeutics, though some have been halted in recent years because patients have experienced adverse events.

In an instance involving one company called Bluebird bio and two patients, the FDA has determined that the treatment did not cause the adverse events. The FDA put a hold on a trial testing a sickle cell disease treatment; one trial participant developed acute myeloid leukemia (AML) and another was diagnosed with myelodysplastic syndrome (MDS), which can lead to AML. But an investigation has shown that the patient's AML was not treatment-related, and the diagnosis of MDS was incorrect; the patient actually had transfusion-related anemia. This trial resumed in 2021.

After another patient developed persistent anemia, the company voluntarily halted the trial. This case seems to have been related to the patient's genetics, however, and not treatment. The testing will now continue.

Another biotech company called Graphite has voluntarily halted its trial of nula-cel, a CRISPR-based gene therapy that aimed to correct a genetic mutation that causes SCD. The process was meant to identify the portions of the genome that carried the mutation, excise them, and replace them with the correct sequence. The first patient in the trial has experience an unexpected adverse event, in which low blood cell counts occurred for a prolonged period of time, a condition known as pancytopenia. The patient has had to receive ongoing transfusions and growth factor treatment. Graphite has concluded that this event was likely to have been caused by nula-cel.


The company is now investigating whether there are modifications that can be made that will reduce the risk of pancytopenia. They have also said that they will not be filing an investigational new drug application for a beta-thalassemia treatment called GPH102 in mid-2024.

Unfortunately, events like this may also hamper any efforts to streamline the review process for experimental drugs.

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Schedule14 Jun 2024