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Landmark’s CRISPR trial shows promise for fighting deadly disease

3D illustration of the CRISPR–Cas9 complex.

The CRISPR–Cas9 complex (white and blue) is able to cleave DNA (green), disabling disease-causing genes.Credits: Ella Maru Studio/Science Image Library.

Preliminary results from a pivotal clinical trial suggest that CRISPR–Cas9 gene editing can be applied directly to the body to treat disease.

This study is the first to show that the technique is safe and effective if the CRISPR–Cas9 component, in this case, targets proteins produced mainly in the liver. will be injected into the bloodstream In this trial, six patients had a rare and life-threatening condition known as Transthyretin amyloidosis is treated only once with gene editing therapy. All of them experience reduced levels of the disease-related malformed protein. Those who underwent two higher doses of the test saw an average 87% drop in levels of a protein called TTR.

The treatment was developed by Intellia Therapeutics of Cambridge, Massachusetts, and Regeneron from Tarrytown, New York. New England Journal of Medicine1

and presented at the Peripheral Nerve Society online meeting on June 26.

Previous results from the CRISPR–Cas9 clinical trial have suggested that the technique could be used in cells that have been eliminated from the body. The cells were edited and then merged back into the study participants. But being able to directly edit genes in the body opens the door to a wider range of diseases.

“It’s an important moment in the field,” said Daniel Anderson, a biomedical engineer at the Massachusetts Institute of Technology in Cambridge. “It’s a new era in medicine.”

incurable treatment

Transthyretin amyloidosis occurs when TTR protein molecules fold into the wrong shape and coagulate. cause fibers that interfere with organ function The disease primarily attacks the heart and nerves. The genetic form of the condition affects about 50,000 people worldwide. More than 100 mutations in child genes linked to transthyretin amyloidosis

This condition can cause heart disease, pain, and death. And until recently, doctors were unable to cure it, says Julian Gillmore, a nephrologist at the Royal Free Hospital in London. “It’s an extremely scary disease,” which has treated people with various forms of amyloidosis. for about 25 years, said, “A few years ago I just saw them get worse and die.”

But transtyretin amyloidosis has emerged as a prime target for new medical technologies aimed at disabling disease-causing genes. It is clearly linked to the production of a particular protein – it shuts down the production of that protein. and the symptoms of the disease stopped progressing and in some cases reversed.

In 2018, the U.S. Food and Drug Administration approved two drugs to treat transthyretin amyloidosis, both of which reduce TTR production by targeting the encoded messenger RNA. Although these drugs reduce TTR by about 80% and prolong survival. But these drugs must be used regularly to lower TTR levels and do not always stop the progression of the disease.

Most of the TTR protein is produced in the liver. which is an organ that easily absorbs medicines from the blood Such features are key, although CRISPR–Cas9 is hailed as a new approach to disease treatment. But there are limitations. The technique requires a DNA-cutting enzyme called Cas9 and a piece of RNA called guide RNA to guide it to the proper location in the genome. These must be packaged in a way that prevents them from deteriorating and must be transported to the site in the body where they need it.

Intellia encapsulates the RNA molecule that encodes the RNA guide and Cas9 protein in biomolecule nanoparticles called lipids, which can be absorbed by the liver. child gene; The cellular DNA repair process repairs the broken parts. But they often make mistakes that can turn off the gene and stop the production of the TTR protein.

One month after treatment, TTR production decreased in all participants. In one person taking the higher of the two doses tested, there was a 96% reduction, an effect that Gillmore, the trial’s researcher, found particularly exciting. Current treatments can reduce TTR by up to 80%, but he says that therapy that further lowers TTR production increases the chances that patients’ symptoms will stop worsening and may lead to improvement.

John Leonard, President of Intellia says, “When you get a number like 96%, that’s your starting point to give your body a chance to cleanse the build-up.

bone marrow and others

Researchers will eagerly await additional input from the participants, Anderson said, and will want to know how all the participants were over a longer period of time. But the current results are enough to fuel hope that CRISPR–Cas9 can help treat not only disease, but also disease. transthyretin amyloidosis, but also other symptoms

Intellia has also been shown to deliver CRISPR–Cas9 components to cells in the bone marrow in mice. Leonard said the company is keen to develop treatments for sickle cell anemia. It does not require the laborious and risky bone marrow transplant used in ongoing gene editing trials for the disease.

Another company is Editas Medicine in Cambridge. Massachusetts has encoded the CRISPR–Cas9 component into a inactivated virus. Editas is testing this in people with a genetic predisposition to blindness. But the virus must be injected directly into the eye. which requires gene editing

Techniques for delivering CRISPR–Cas9 components to parts “The list is growing,” he said. “I’m optimistic that we’ll see more broad-based applications of genome editing.”

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