The Dawn of CRISPR Therapies: What’s New?

“As I write this, the world around us is being revolutionised by CRISPR, whether we’re ready for it or not,” writes Jennifer Doudna, the co-inventor of CRISPR gene editing technology in her book A Crack in Creation. As a species, we now have the power to crack the code of life; “the distinction between ‘natural’ and ‘unnatural’ has been obscured.”

CRISPR (clustered regularly interspaced short palindromic repeats) are repetitive DNA sequences found in bacteria. They are transcribed to RNA as a defence mechanism against viral infection. The RNA guides nuclease enzymes, such as Cas9, to viral DNA, cutting them out and essentially acting as molecular ‘scissors’. This ability to cut DNA at specific points is the basis of the CRISPR-Cas9 genetic modification system. The discovery in the 2000s revolutionised the world of genetic engineering. Healthcare, agriculture, and scientific research all became avenues in which CRISPR technology could expand knowledge and innovation

12 years after Emmanuelle Charpentier and Jennifer Doudna had developed the gene-editing technique, why hasn’t everything changed?

So far, the progress has been behind the scenes. Developing a therapy is a long and arduous process — an effective and reliable technique must be created and refined, tested on animals, approved for several rounds of clinical trials, and then approved again before it can be used on the public. There is currently only one CRISPR therapy that has reached this last stage. But the finish line is fast approaching for many. 

Many CRISPR-Cas9 therapies have had successful clinical trials. In 2023, the editing tool was used on a small group of patients with hereditary angioedema, a genetic disorder that can cause debilitating swelling in multiple areas of the body. The CRISPR editing machinery was packaged into nanoparticles that were injected into the bloodstream and were designed to find their way to the liver. In the liver they locate the prekallikrein-encoding KLKB1 genes in the individual cells and disable them. This results in less prekallikrein being produced, which in turn reduces the amount of bradykinin released, thus preventing inflammation. The clinical trial had very positive results, causing a reduction in symptoms in 95 per cent of the patients. 

The treatment has been used for a larger second clinical trial, with plans for a third next year. However, despite its success, the treatment is unlikely to become widely available any time soon due to its high cost. Each shot can cost up to £1.5 million, making one-shot gene therapies some of the most expensive medicines in the world.

In November of last year, Casgevy, a one-shot gene therapy used against sickle cell disease, became the first CRISPR-Cas9 therapy to be approved. First approved by the MHRA in the UK, the NHRA in Bahrain and the FDA in the US soon followed suit. Sickle cell disease, a hereditary disorder that causes red blood cells to become misshapen, affects 20 million people worldwide. The first stage of the new therapy involves removing blood-producing stem cells from the patients. These are edited using CRISPR-Cas9, which cuts at a specific spot on the BCL11A gene to disable it. This is a gene that stops the production of foetal haemoglobin. The modified stem cells are then quality-tested and administered to the patients. The outcome of the therapy is the production of healthy foetal haemoglobin in patients with sickle cell disease, increasing the amount of oxygen their red blood cells can carry and greatly reducing symptoms.

Unfortunately, approval and accessibility are not adjacent. The price of Casgevy for each patient is currently set at £1.7 million. This is partly due to the complex development and manufacturing process, but the price is also influenced by the reasoning that the one-off treatment should cost the equivalent of the several years of treatment that would otherwise be necessary. 

The applications of CRISPR-Cas9 technology are not limited to humans. There are many exciting projects in the works aimed at improving the efficiency of farming practices or tackling environmental problems. One such project is the Woolly Mammoth Revival project by the company Revive & Restore. The aim is to bring back woolly mammoths from extinction to repopulate the tundras of Siberia and North America, areas which have been warming rapidly and releasing carbon dioxide. Woolly mammoths had significant impacts on the tundra ecosystem, maintaining grasslands by breaking up moss, knocking down trees and fertilising the earth with their droppings. The project hopes that woolly mammoths will restore the grasslands, prevent soil erosion and act as a carbon sink. 

Revive & Restore are using CRISPR-Cas9 to modify the DNA of Asian elephants, which are closely related to the woolly mammoth, using ancient woolly mammoth DNA to identify genes that would allow the modified hybrid species to live in the far north. 

The possible applications of CRISPR technology are limited only by the human imagination. The CRISPR revolution is a slow one, but big changes are on the horizon, with therapies and projects set in motion years ago finally coming to fruition.

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