DNA scissors cut into a living human for first time—with overwhelming success
The first patients at Amsterdam UMC have been successfully treated with the DNA scissors CRISPR-cas. Patients with angioedema, or fluid accumulation, have been declared disease-free and stopped taking medication. “I wouldn’t have dreamed a few years ago that we could already achieve this now.”
“Overwhelmed,” was how internist Danny Cohn felt when the experimental clinical treatment proved successful. Ten patients with the hereditary disease angioedema turned out to be disease-free after one treatment with CRISPR-cas.
The publication appeared last night in the professional journal New England Journal of Medicine. Cohn comments: “We have never been so close to the ultimate treatment goal: a normal life for patients with hereditary angioedema. I wouldn’t have dreamed a few years ago that we could already achieve this now.”
The patients with hereditary angioedema—the hereditary disease in which sudden swelling can occur anywhere in the body, sometimes resulting in death, hereinafter referred to as angioedema—were given a three-hour treatment with a CRISPR-cas infusion. Two of these patients were treated at Amsterdam UMC. Up to six months after treatment, patients no longer experience symptoms with no serious or lasting side effects.
This is revolutionary, because CRISPR-cas, the molecular scissors that can cut and paste pieces of DNA and was awarded the Nobel Prize in 2020, had not previously been used in the Netherlands for treatment inside the body of patients. Cohn says: “The scissors are doing their cut-and-paste work in the Netherlands for the first time in the human body, in vivo. As far as I know, this has only been done once before worldwide.” That research was again conducted with the participation of research institutes such as the Cambridge University Hospitals and the University of Auckland.
Functional healing
Yet cure is not the right word, Cohn explains further. “I call it functional healing. That’s because the hereditary error in the DNA is still there. Thus the disease is not gone from the patient, although the patient no longer experiences symptoms.”
Here’s why. People with the disease angioedema have an inherited error in their DNA that prevents the production of a certain protein. That protein is crucial for inhibiting the production of kallikrein, a messenger protein produced in the liver that causes swelling. If kallikrein is not present, there are no swellings, researchers from Amsterdam UMC previously discovered.
So to combat the swelling, the production of kallikrein must be reduced. To do this, the researchers use CRISPR-cas, which can cut out the piece of genetic material that tells them how to make kallikrein and then glue the DNA back together. Cohn says: “So we don’t fix the mistake in the DNA that causes angioedema, but we inhibit the messenger protein kallikrein, which relays the message that swelling should occur.’
Address label
To ensure that CRISPR-cas is delivered purely and exclusively to the liver, the researchers packaged it in fat globules provided with an “address label.” Receptors on liver cells recognize that label and absorb the fat globule into the cell.
Had the researchers really wanted to cure the disease, they would have had to replace the entire pathogenic gene. Cohn says: “That piece of genetic material is too big to put into a small fat globule. That can only be done with a harmless virus or a new delivery system that is yet to be developed but still in the future in human patients.”
Another way to completely remove an inherited disorder from the DNA is to harvest stem cells from the patient and treat them outside the body (ex vivo) with CRISPR-cas and then return them. Last November, medical approval was given to treat sickle cell disease this way for the first time.
So in the case of angioedema, patients can still transmit the disease to offspring, as the DNA in the reproductive cells remains unaffected. But there is the consolation that by then, there will be proper treatment for their offspring.
Other hereditary diseases
The research in angioedema paves the way for the treatment of all kinds of other hereditary diseases with CRISPR-cas. Says Cohn: “I specialize in angioedema, but when I look at the literature, the applications are endless. This includes neurological diseases, blood clotting diseases, muscle diseases but also tumors.
Meanwhile, more than two patients at Amsterdam UMC have already been treated with the CRISPR infusion against angioedema. All patients will continue to be monitored over the next 15 years, but Cohn does not expect to see a relapse. “The effect of the treatment is also visible in new liver cells, so it truly is permanent.”
