Injection of a CRISPR-Cas9 Based Treatment into the Bloodstream May Cure Transthyretin Amyloidosis a Rare Genetic Disease

For the first time, researchers have injected a CRISPR-Cas9 based treatment into the blood of sick patients. This has reduced the concentration of the toxic protein that is responsible for their disease (Transthyretin amyloidosis).



The CRISPR-Cas9 molecular scissors have revolutionized gene editing and the applications seem endless. Doctors see it as the treatment of the future for genetic diseases. Although it has proven its efficacy in in vitro studies in cell cultures, its in vivo application in humans and animals still faces many hurdles.

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But scientists at biotech companies Regeneron Pharmaceuticals and Intellia Therapeutics have taken a major step forward. In a study published in NEJM, they present interim results from their phase 1 clinical trial of a CRISPR-Cas9-based treatment for Transthyretin amyloidosis. Their results are surprising.

Acting at the source

Transthyretin amyloidosis is characterized by the accumulation in the body of an abnormal form of transthyretin, the vitamin A-carrying protein. This dysfunction may occur sporadically, especially in the elderly, or it may be the result of an inherited genetic mutation. The only gene involved is TTR, located on chromosome 18. Doctors have identified about a hundred mutations in this gene that are capable of causing a pathological form of transthyretin, which accumulates in the nerves as well as in the heart and kidneys. Transthyretin amyloidosis is a fatal disease with an average life expectancy of about ten years after diagnosis. There are treatments that slow the progression of the disease, but they do not act at the source. CRISPR-Cas9 treatment does.

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Elimination of the mutated gene

Scientists at Regeneron Pharmaceuticals and Intellia Therapeutics developed the following construct: a fatty nanoparticle which protects a guide RNA specific to the TTR gene, as well as another RNA molecule, this time a messenger RNA that codes for the Cas9 protein, the scissors that cut DNA. The nanoparticles were specifically designed for use in hepatocytes because the liver is the organ that produces most (95%) of transthyretin.

This treatment, called NTLA-2001, is injected into the bloodstream and reaches the liver. Upon entering the cells, the fatty capsule dissolves and releases its contents. The Cas9 mRNA is translated into protein and combines with the guide RNA to form a functional complex. The latter enters the nucleus and targets the TTR gene. It makes a double-stranded cut in the DNA. The cell attempts to repair this lesion by gluing the two ends together, thereby erasing the original sequence. As a result the gene can no longer produce transthyretin.

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This approach was tested in six volunteers with transthyretin amyloidosis at a hospital in Auckland (New Zealand) and London (England). The four men and two women received either 0.1 mg/kg or 0.3 mg/kg of NTLA-2001 intravenously. The researchers closely monitored the effect of the treatment on the amount of transthyretin in the serum. After 28 days, the protein concentration decreased by 52% at the lowest dose and by 87% at the highest dose. The treatment did not cause any serious side effects.

Still More questions need to be answered

Altering a gene in this way can have far-reaching consequences. One of the biggest fears about the CRISPR-Cas9 system is that the scissors will cut in a different place than intended, which could lead to unintended mutations with consequences that are difficult to predict. The experiments performed here in human hepatocytes did not result in induced off-target mutations. The only changes observed in the DNA were due to repair which the scientists believe is unlikely to cause problems.

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Although the amount of transthyretin was reduced, the positive effect of the treatment on disease symptoms has not yet been demonstrated. The follow-up of the patients is not yet long enough to draw any conclusions, so we will have to wait months. In addition, only six people have benefited from this treatment. That is too few to conclude that the treatment is safe and effective for everyone. Still, these results suggest that treatment of genetic diseases with CRISPR-Cas9 is within the realm of possibility.


Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN)



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