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CRISPR injected into the blood treats genetic disease

For the first time, researchers have injected CRISPR into the blood of people with a genetic disease and shown that it can ease symptoms of disease.

Transthyretin amyloidosis

Transthyretin amyloidosis, also known as ATTR amyloidosis, is a progressive fatal disease characterised by the accumulation of amyloid fibrils in tissue. These fibrils are composed of misfolded transthyretin (TTR) protein. This condition can be both acquired and hereditary. The acquired form, also referred to as wild-type ATTR amyloidosis, is an increasingly recognised form of cardiomyopathy and heart failure. The rarer hereditary form, known as variant or hereditary ATTR (hATTR) amyloidosis, can be caused by over 100 different pathogenic mutations in TTR. This form affects approximately 50,000 individuals worldwide and has an autosomal dominant pattern of inheritance. ATTR amyloidosis is progressive and ultimately results in death within a median of 2-6 years after diagnosis.

Current therapies rely on reducing ongoing amyloid formation through stabilising the tetrameric form of TTR or through inhibition of TTR protein synthesis. These therapies produce symptom relief and prolong survival. However, they require long-term administration to maintain their effects.

CRISPR-Cas9-based in vivo gene-editing therapy

In a recent paper, published in the NEJM, researchers presented the results from an ongoing phase I clinical study exploring the safety and pharmacodynamic effects of a new CRISPR-Cas9-based in vivo gene-editing therapy (NTLA-2001). In the trial, four men and two women with transthyretin amyloidosis aged 46-64 were injected with this therapy. The therapy specifically contained a lipid particle carrying two RNAs. The first encoded the Cas protein and the second encoded the guide RNA targeting the TTR gene.

After 28 days, researchers found that those given the higher of two doses had an 80-96% drop in TTR levels. This is on par or better than the average of 81% with the TTR protein synthesis inhibitor, patrisiran.

Neurologist David Adams of the University of Paris-Saclay, expressed:

“It could be potentially the first curative treatment for this hereditary disabling and life-threatening disease.”

While it could take months for patients’ symptoms to lesson, there were a few short-term side effects reported. In addition, other unknown long-term effects may also arise over time due to the potential off-target effects of CRISPR. Nonetheless, this lipid-based mRNA approach is potentially safer than using viral vectors.

Overall, this study paves the way for treating other diseases with CRISPR, either by gene knockout or eventually by modifying the gene.

Image credit: By Teka77 – canva

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CRISPR / Genetic Variants / Rare Diseases