CRISPR Injected into Blood Treats a Genetic Disease for the First Time Ever

This paves the way for correcting gene defects anywhere in the body.
Ameya Paleja

Ever since its discovery, CRISPR-Cas9 gene editing has been pushing the boundaries of genome modifications. Just last month, we reported how researchers were using CRISPR to fix cholesterol in monkeys.  Now, in a major breakthrough, researchers at University College London (UCL) injected CRISPR into the blood of six people with a genetic condition. Three of them showed promising results, paving way for further trials using this approach. 

Transthyretin amyloidosis is a slowly progressing condition caused by a mutation - a genetic defect in the TTR gene. The mutation causes the transthyretin protein produced by liver cells to misfold leading to amyloidosis, which consists of abnormal deposits of protein in the body. Transthyretin amyloids occur in the nerves connecting the brain and spinal cord to muscles and sensory cells. This leads to a loss of sensation such as pain, heat, and touch in the body's extremities.

The deposits occur over the years and symptoms can appear anywhere between the age of 20 to 70.  The condition occurs rarely in people of European descent but is seen more frequently in Africa. Patisiran is an approved drug to treat this condition. 

Most CRISPR-related treatments involve treatment of the cells in-vitro, or outside the body, and then they are injected into the target organ. Using CRISPR in-vivo, or inside the body, is an entirely different ball game, requiring the transport of the whole editing assembly inside the cells. 

Researchers at Regeneron Pharmaceuticals and Intellia Therapeutics developed an injectable CRISPR treatment with a simple operation. They used messenger RNAs (mRNAs), which carry instructions for making proteins. Since the host cell can use the mRNAs to make its own proteins, researchers simply needed to send enough information to enable CRISPR editing inside the cell.

To this effect, they injected two messenger RNAs (mRNAs), one identified the mutation on the TTR gene and one made the Cas protein that can cut the DNA at the directed site. Since liver cells actively uptake foreign particles and are the site of origin for the disease, the task at hand became easier. 

The mRNAs were encased in lipid particles, which were taken up by the liver cells, allowing the mRNAs entry inside the cell. Once there, the cellular machinery made the necessary Cas protein, which cut the mutation site recognized by the other mRNA. The in-house DNA repair mechanism kicked in and repaired the cut site but this time, left the gene out, thereby stopping the production of misfolded protein. 

Three individuals who received higher doses of this treatment showed a drop in TTR protein levels in the range of 80-96 percent after 28 days of treatment. This is comparable to the 81 percent drop seen with the approved drug, patisiran. Symptoms might take a few months to subside. 

Jennifer Doudna, Nobel Laureate for her discovery of CRISPR, told Science magazine that this research is “a critical first step in being able to inactivate, repair, or replace any gene that causes disease, anywhere in the body.”

Going by the current pace of developments in the field of CRISPR editing, woolly mammoth revival may not be that far away. 

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