Taking a pair of scissors to our DNA
How new gene-editing technology is set to revolutionise the fight against disease
Agene-editing technology called Crispr Cas-9 is set to transform the lives of millions of people suffering from genetic diseases by cutting out genes from our DNA that cause disease and replacing them with normal, healthy genes.
The ability to change genes that are broken or defective and causing disease has been something scientists have been trying to do since the 1980s. However, until the arrival of Crispr it wasn’t possible to correct a disease-causing gene.
“Crispr to me is a DNA scissors, a way of going in, targeting very specific pieces of DNA and being able to cut those apart,” explained Dr Breandan Kennedy, based at the Conway Institute, UCD, who is using the technique to address vision loss and blindness.
“You can cut the pieces away, you can put pieces in, you can remove pieces, you can add pieces,” said Dr Kennedy. “It is a bit like an electrical cable where you splice out a piece that might be damaged and you put in a new piece.”
Of course, we have our genes to thank for our eye colour, height, perhaps even our personality, but also for our susceptibility to disease. For example, one in 19 Irish people carry a gene that causes cystic fibrosis, a condition affecting our lungs and shortens lives, while one in 5,000 of us have genes for Long QT Syndrome (LQTS), a condition affecting the heart, and which can lead to sudden death.
Some diseases, such as cancer, are thought to be caused by the action of many genes, while others, like cystic fibrosis and LQTS are due to one, or a few genes, and could, therefore, be more easily identified and “corrected” by Crispr. Meanwhile, the speed at which Crispr is being deployed in laboratories around the world to fight various diseases is breathtaking.
For example, Dr Patrick Harrison, based in the department of physiology at UCC, is using Crispr to address his main research interest: CF. He is working on developing methods to make the gene-editing tool even more efficient at replacing the genes that can cause CF with normal genes.
The arrival of new drugs such as Orkambi and Kalydeco have changed the lives of people with CF for the better, said Dr Harrison, and in coming years the vast majority of people with CF will have a drug available to them that improves their symptoms. That will leave 5 per cent of people with rare forms of CF still without a treatment option. For them Crispr may prove to be a godsend, while also being attractive to others with CF who don’t want to take drugs every day.
“Small molecules - as drugs - will sort out 90 to 95 per cent of people with CF, but they will still have to take this medication for the rest of their lives,” said Dr Harrison. “If you have gene therapy, you might have a one-hit thing, where this could last for a year, it could last for five years, it could last for life.”
Dr Terry Prendiville, paediatric cardiologist at Our Lady’s Hospital for Sick Children Crumlin, works with children who have inherited cardiac conditions such as LQTS, which put them at risk of sudden cardiac death. He is working with scientists at the Remedi centre in NUI Galway to use Crispr to correct the genetic defects in these young patients and allow them to live normal lives.
There are some 30 babies per year born in Ireland with LQTS, while 500 babies are born with inherited cardiomyopathy. “These children are born with a vulnerability that places them at risk of a heart rhythm problem,” said Dr Prendiville. “Sometimes these children will present with collapse events, or faints, or symptoms of palpitation, but the dreaded presentation can be sudden, unexpected death.”
“We have taken skin samples from volunteer children and adults, and we have grown them in a dish,” explained Dr Prendiville. “We are in the process of applying this Crispr Cas-9 to correct their long QT syndrome in a dish.
“The ultimate goal might be to administer what would be equivalent of a vaccination,” said Dr Prendiville, “and in that vaccination a virus would be administered to the patient that would repair their heart cells and effectively cure them of their risk of a life-threatening arrhythmia.”
Luke O’Neill is professor of biochemistry at TCD, and he too has adopted Crispr to tackle diseases caused by a faulty immune system. The goal now, he said, is to use Crispr to tackle diseases that are caused by single genes, but down the road the technology could be used to tackle more complex diseases.
“There are very specific cancers where one gene is defective and they are the first ones to go at,” said Prof O’Neill. “The trouble is that many other diseases have multiple genes, so the question is ‘Can you correct more than one gene?’ – that might be more of a challenge, but you never know.
“If this technology continues you might well be able to fix multiple different genes in different diseases,” said Prof O’Neill. “One disease we work on is rheumatoid arthritis. There is about 70 genes implicated in that disease.
“Can you imagine if we can correct all those, wouldn’t that be wonderful? The dream is that all these genetic defects will ultimately be corrected one day.”
‘‘ Small molecules - as drugs will sort out 90 to 95 per cent of people with CF, but they will still have to take this medication for the rest of their lives. If you have gene therapy, you might have a one-hit thing, where this could last for a year, it could last for five years, it could last for life
Main above: ■ Christina Kenny with her mother Alison, who died from complications of CF; Above right: Dr Breandan Kennedy, who is based at the Conway Institute, UCD. Above left: Prof Luke O’Neill in a laboratory in Trinity.