Administering gene-editing treatment directly into the body could be a safe and effective way to treat a rare, life-threatening condition.

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Previous gene-editing therapies involved removing cells from the body, revising their genetic material, then re-infusing the cells. A breakthrough clinical trial now proves that gene-editing components called CRISPR-Cas9 can be injected directly into the body with astonishing results, offering hope to those suffering from at least one painful, life-threatening Disease. Scientists think similar therapies could improve the lives of countless others.

Take-Aways

• Early clinical trial data suggest that CRISPR-Cas9 gene editing can successfully treat life-threatening disease.
• Previous to this experimental therapy, transthyretin amyloidosis was virtually untreatable.
• While regarded as revolutionary, the new CRISPR-Cas9 therapy presents limitations.
• Researchers look forward to data on how additional trial participants fare over time.

Summary

Early clinical trial data suggest that CRISPR-Cas9 gene editing can successfully treat life-threatening disease.

A groundbreaking study shows that the infusion of a gene-editing substance that attacks an errant protein made by the liver can prove effective and safe.

In a clinical trial, six subjects afflicted with a rare, fatal medical condition called “transthyretin amyloidosis” received one treatment of CRISPR-Cas9 gene-editing components. All patients saw a reduction in a “misshapen protein” called TTR, which is endemic to the disease. Higher doses of CRISPR-Cas9 related to an approximate 87% decline in irregular protein levels.

“It’s an important moment for the field. It’s a whole new era of medicine.” (Daniel Anderson, biomedical engineer at Massachusetts Institute of Technology)

Intellia Therapeutics of Cambridge, Massachusetts, working with Regeneron of Tarrytown, New York, developed the treatment and published results in The New England Journal of Medicine. Other CRISPR-Cas9 trials have used a technique where cells are removed from the body, edited and then re-infused. Editing genes within the body opens the door to treating a wider range of diseases.

Previous to this experimental therapy, transthyretin amyloidosis was virtually untreatable.

The disease presents with molecules of TTR protein folding into aberrant shapes and clumping together. The resulting fibers especially affect nerves and the heart. The result is often pain, heart disease and death. About 50,000 people suffer from a hereditary form of the disease, with at least a hundred mutations linked to it. Treatments were virtually absent until recent years.

“It’s an absolutely awful disease. Up until a few years ago, I just watched them get worse and die.” (Julian Gillmore, nephrologist at Royal Free Hospital, London)

Transthyretin amyloidosis presents a hopeful target for emergent technologies that address diseases caused by faulty genes. In this case, the condition is clearly linked to a specific protein. If protein production can be stopped, the disease could be halted or even reversed.

The US Food and Drug Administration approved a pair of transthyretin amyloidosis drugs in 2018. Both reduce TTR protein production by about 80%, by targeting its messenger RNA. Patients enjoy longer survival rates, but must consistently take the medications throughout their lives.

While regarded as revolutionary, the new CRISPR-Cas9 therapy presents limitations.

TTR protein is primarily produced in the liver, an organ that uptakes medicines from the bloodstream. The new treatment requires a combination of the “DNA-cutting enzyme, called Cas9” with “guide RNA” to be placed precisely within the genome. The materials must be shielded to prevent degradation.

Intellia Therapeutics wrapped RNA molecules “coding the guide RNA and the Cas9 protein” into nanoparticles of lipids, which the liver can process. The guide RNA directs Cas9 to clip the TTR gene. The body’s DNA-repair defenses then attempt to fix the damage, but mistakes made in the process can disable TTR, stopping its production.

“When you get to numbers like 96%, that’s where you start to give the body a chance to clean up what has been deposited.” (John Leonard, Intellia Therapeutics president)

One month following treatment, all participants experienced reduced TTR production. In one patient receiving a higher dosage, TTR levels fell by 96%. That result beats typical treatments that reduce the protein by about 80%. A more aggressive TTR reduction provides hope for arrested disease progression, if not improvement.

Researchers look forward to data on how additional trial participants fare over time.

The new gene-editing technique may one day be used to treat a variety of conditions. One target is sickle-cell anemia. Currently, gene modification for that disease requires risky bone marrow transplants. Intellia has delivered CRISPR-Cas9 to bone marrow cells in mice.

“The list keeps growing. I’m optimistic that we’re going to see much broader application of genome editing.” (Daniel Anderson)

Editas Medicine of Cambridge, Massachusetts, is running tests that encode CRISPR-Cas9 into a “disabled virus.” Their initial objective is to treat a genetic illness that causes blindness. The substance must be directly injected into the eye for gene alterations to occur. Techniques utilizing CRISPR-Cas9 are progressing at a brisk pace, and should soon be available to address a variety of obstinate health conditions.

About the Author

Heidi Ledford is a senior reporter for Nature. She specializes in biomedical topics such as cancer research, drug development, biotechnology and CRISPR.

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