In June 2021, companies Intellia Therapeutics and Regeneron Pharmaceuticals reported they had used CRISPR to alter a disease gene in humans for the first time – the transthyretin (TTR) gene – in patients with TTR amyloidosis. The treatment sharply reduced levels of toxic TTR protein, the primary cause of the disease. However, as the early observations were presented after just 28 days from treatment, the long-term effects were unknown.
Now, follow-up analysis reveals that reductions of up to 93 percent in TTR protein are maintained up to a year following treatment, with no major side-effects. 'We've been waiting for the definitive answer,' said Dr John Leonard, Intellia president and CEO, 'What we show is that pretty much what you get on day 28 is what you're going to have thereafter.'
Heritable differences in the TTR gene can cause the TTR protein to misfold and build-up in nerves and organs, leading to TTR amyloidosis. If untreated, this can cause nerve pain, numbness, and heart failure as adults.
The CRISPR genome editing treatment works by injecting lipid particles into the blood which are directed to the liver, where TTR is produced, to drop off a messenger RNA coding for CRISPR's DNA-cutting enzyme, Cas9, and an RNA strand to guide the enzyme to cut specifically at the TTR gene. After the gene is cut, the cell will repair the break imperfectly and introduce errors, disabling TTR production.
No major side-effects were observed across all 15 people in the study. One patient did experience vomiting, although they had prior medical history of vomiting due to gastroparesis, a common symptom of TTR amyloidosis. All patients now receive vitamin A supplementation as TTR normally plays a role in vitamin A transport.
Until now, there were no improvements in disease symptoms, and it is unknown whether improvements will follow or if the treatment may just stabilise the disease. The researchers hope that as the disease protein is no longer deposited, the body's natural defences will begin to work to clear out the build-up. As currently approved drugs that reduce TTR levels by 80 percent do eventually lead to symptom improvements, there is some optimism that CRISPR genome editing can do the same with a one-time treatment.
'I think people are generally assuming that the clinical outcomes will follow,' said Professor Kiran Musunuru of the University of Pennsylvania, who researches CRISPR treatment strategies for heart disease.
The researchers plan to expand their study, including patients with a cardiac form of the disease. They are also using the CRISPR approach to edit a gene involved in hereditary angioedema, a disease which causes severe swelling in the limbs and airways.