Gene editing: a therapy with masses of potential, but not only in treating cancer…

Last week gene editing hit the news with the story of young leukaemia patient Layla and a pioneering treatment at Great Ormond Street. Here Dr Anoushka de Almeida, Head of Research at the Cystic Fibrosis Trust, talks about the science behind the story, and the ground-breaking work being funded by the Trust into using genetic editing for treating cystic fibrosis.

We have recently heard on the media of clinicians at Great Ormond Street Hospital using the revolutionary technique of gene editing to treat a little girl, Layla, diagnosed with an aggressive cancer of the bone marrow. All other conventional treatments failed and this was Layla and her family’s last hope – and it seems to have worked.

So what did they do to produce such a miracle? Layla’s doctors teamed up with researchers at UCL, led by Prof Waseem Qasim, who has developed a novel approach to gene editing in immune cells (T-cells). This approach involves taking donated T-cells from a healthy person, modifying the genome using gene editing to enable them to attack cancer cells, and then introducing them into the body. Previously, these cells had only been tested in mice, so Layla was the first human to receive them. The  gene editing technique they used involved using a pair of 'molecular scissors’, a kind known as TALEN proteins, to ‘switch off’ certain receptors, making sure that the modified T-cells leave the healthy cells alone and only attack leukaemia cells. Genes were also edited out to make the new cells ‘invisible’, so that they wouldn't be destroyed by other leukaemia drugs.

 

It is still early to say whether Layla has been completely cured. The pharma company Cellectis, who collaborated with Qasim, plans to start full clinical trials early in 2016, the results of which will hopefully confirm that this isn’t just a one-off. If they are successful, this is a huge step forward for treating leukaemia and other cancers, as well as other conditions…

This leads me on to talking about the research that’s currently underway using gene editing in cystic fibrosis…

As we know, cystic fibrosis is caused when there are mutations in both copies of the CFTR gene. Recent studies have shown that the most common CF-causing mutation, F508del, can be corrected using a gene editing technique called ‘CRISPR/Cas9’ (a different method to what they used for Layla – but principally the same). The first step in this technique is to cut out the dodgy bit of genome using the ‘molecular scissor’ complex, and the second step is to repair it by using a donor DNA molecule containing the correct, non-faulty sequence. Now, this all works well in isolated cells outside the body, but the efficiency of the repair is very low. Also, difficulty arises when delivering both the molecular scissor complex and the donor DNA into the correct place in the body.

A different approach is being investigated by Dr Patrick Harrison and colleagues at University College Cork. This work, which the Cystic Fibrosis Trust is co-funding with the Cystic Fibrosis Foundation in the US, involves focusing on a small group of three rare CF-causing mutations. (These mutations basically disrupt the processing of the messenger RNA molecule which is normally needed to make the CFTR protein in cells). In all three cases, there is an extra sequence in the genome which interferes with the normal processing. Dr Harrison’s team is exploring using the gene editing approach simply to cut out this extra piece in the genome region that causes the problem. This CRISPR ‘knock-out’ strategy is more efficient than repair, and only requires delivery of just the molecular scissor complex; no donor DNA is required.

Dr Harrison’s group has teamed up with groups in Europe and the US to take this work further so that they can determine if all this hard work eventually leads to the normal CFTR protein being produced, resulting in normal functioning of the particular lung cells in cystic fibrosis.

So, off the back of the break-through in little Layla, gene editing has re-entered the limelight. It can be safely said that it is not only a promising prospect for cancer such as leukaemia, as her case unquestioningly demonstrates, but also for genetic conditions like cystic fibrosis. The Cystic Fibrosis Trust is fully supportive of this therapy and sees its exciting potential, and we would be keen to engage in further cutting-edge research in this area of genetic therapies.