Treating the Incurable: Using Gene-Editing to Cure Transthyretin Amyloidosis

Image Credit: Sangharsh Lohakare via Unsplash

Andrea Beyer investigates a modern clinical trial in which CRISPR-Cas9, a gene editing technology, is injected directly into the bloodstream of patients suffering from a rare genetic disorder.

Emmanuelle Charpentier and Jennifer A. Doudna were jointly awarded the prestigious Nobel Peace Prize in Chemistry in 2020 for their 2012 research on the DNA editing technique CRISPR-Cas9, which is an innovative technology that allows researchers to modify specific regions of a genome by cutting, adding, or otherwise changing a DNA sequence. CRISPR-Cas9 is an abbreviation for Clusters of Regularly Spaced short Palindromic Repeats and CRISPR-associated protein 9. The gene editing technology enables rapid genome editing and the discovery has significantly changed the landscape of diseases under investigation that CRISPR could help cure such as cancer, sickle cell disease, and diabetes, to name a few.

 We sat down to chat with Dr Rory Johnson, associate professor in the school of biology and environmental science at University College Dublin and the founder of the Genomics of Long noncoding RNAs in Disease (GOLD LAB). Dr Johnson’s lab uses CRISPR-Cas as a research tool for manipulating genes and DNA, particularly as a screening tool to identify new drug targets. As a researcher working with CRISPR-Cas, Dr Johnson’s input on recent human trials using the technology was invaluable. There is a sense of urgency, with one CRISPR trial after another making headlines every month, and when asked if he believed there was a current pressure to work with CRISPR and use it in clinical tests, Dr Johson stated that he did not believe there was explaining the situation as follows: “I don't think that there is a pressure I think that there's a lot of economic opportunity and a lot of medical opportunities because it enables you to stage medical interventions that you couldn't do before so there's been a big race among several groups.” 

 “Since being involved in the trial I have noticed a difference. I don’t have as much numbness in my hands and feet that I used to get and I can go hill-walking with less of a problem.”

One of the most promising trials that employs CRISPR is the one that aims to stabilise and ultimately cure a potentially fatal protein disorder known as transthyretin amyloidosis, distinguished by the accumulation of abnormal protein deposits known as amyloid (amyloidosis) in the body's organs and tissues. The study is promising as trials using CRISPR up to now used ex-vivo (outside the body) methods where cells were removed from the patient, gene-edited and then re-infused into the patient. This trial led by Julian Gillmore from University College London was the first of its kind as NTLA-2001, an in-vivo gene editing therapeutic agent designed to target the TTR gene, was injected directly into the bloodstream, allowing it to travel through the body directly into the liver to find the cells that needed editing on their own. All clinical subjects involved in the interventional study demonstrated a reduction in the quantity of the disease-related protein, levels decreased by an average of 87% in those who received the higher of the two doses tested. 

Patrick Doherty of Gaoth Dobhair, Donegal, was one of the first six patients to receive the gene-editing therapy intravenously to treat transthyretin amyloidosis. Patrick described his initial symptoms as numbness in his fingers and toes and experienced breathlessness whilst doing simple activities such as walking his dog or going up the stairs in his home. Patrick's father died of the fatal disease, and he was suspicious that he might have it as well; unfortunately, his intuition was right. Patrick has provided the following account of his experience after the trial: “since being involved in the trial I have noticed a difference. I don’t have as much numbness in my hands and feet that I used to get, and I can go hill-walking with less of a problem.” 

Dr Julian Gillmore has since led another trial with different people and higher doses, and he shared that in his recent trial, 12 patients with amyloidosis who also had heart failure were treated with NTLA-2001. In an interview with the US Cardiology Review published on the 5th of November 2022, Dr Gillmore stated that all patients had achieved 90% or greater reduction in circulating TTR protein concentration by day 28, and the reduction persisted through to the most recent follow-ups 4-6 months after. To put this figure into context for us students, our beloved hormonal birth control is 99% effective in theory; however, no one takes their pill perfectly; there is no shame in taking it at different times every day; after all, we live busy lives, and as a result, the pill is only 91% effective in reality at preventing pregnancy. Therefore, in terms of the trial, the figure of >90% reduction is extremely promising. 

Often, the disease is so severe that patients are willing to take that relatively controlled risk to have a very high chance of treating their condition.

CRISPR trials are especially exciting because gene editing allows us to potentially cure diseases for which there is currently no treatment. However, there are risks associated, as it involves cutting into human DNA, and we do not currently know the range of potential outcomes. Dr Johnson, on the other hand, emphasised that: “Often, the disease is so severe that patients are willing to take that relatively controlled risk to have a very high chance of treating their condition.”

This study is the first to demonstrate that the method, which in this case targets a protein primarily produced in the liver, is both safe and efficient. Jennifer Doudna, one of the two women that received the Nobel Peace Prize for the CRISPR-Cas9 technology, commented on the clinical trial. "While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place." 

The ongoing trials to treat transthyretin amyloidosis not only demonstrate CRISPR's potential in curing transthyretin amyloidosis, but also open the door to curing other similar incurable diseases like Alzheimer's. We may not know what the future holds, but a future with CRISPR gene editing should be one to be excited about.