A gene-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.

Splice out

“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.”

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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.

Developing methods

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.”

Inherited conditions

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.”

Tackle diseases

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.”

CHRISTINA’S STORY: ‘This would, literally, change lives’

In her final year studying science at UCD, Christina Kenny knew that she wanted to do postgraduate research, but was unsure in what area. Her mother, Alison, who had cystic fibrosis (CF), advised that she do something that she really cared about.

The previous year Christina (23), had done an internship at Queen’s University Belfast involving research into CF and had loved it. She decided that was what she wanted to do, and she set out to find out more about her mum’s condition.

“It seemed like the perfect fit,” recalls Christina. “It was something that I really cared about, and I knew a lot about, so that’s what I did. I started a PhD in cystic fibrosis research.” She started her PhD in September 2015, but sadly her motherAlison passed away on Christmas Day only a few short months later. She was 45.

Alison’s quality of life was badly affected by CF, but her spirits stayed high. “I have no idea how she did it,” said Christina. “She was one of the jolliest, most happy-go-lucky people anyone has ever met. She was a big joker, and was constantly taking the piss out of anything and everything. It never ended.”

After her mother died, Christina went back to study two months later, but it proved to be too early. She felt herself becoming overwhelmed by her loss and decided to put her PhD study on pause, with about two years of it left to run.

“My mother is one of seven children, and three of them have cystic fibrosis,” explained Christina. “My mother’s brother got a transplant when he was around 29. He was the last person to be transplanted with a certain bug called Cepacia and he passed away after the transplant.”

The lung transplants for CF stopped for people with Cepacia, because people were dying, explained Christina. Then, when Alison too got the bug, it meant that transplantation was not an option for her. Furthermore, she had a rare form of CF that meant she was not an ideal candidate for new anti-CF drugs such as Kalydeco.

If Crispr had been developed in time for Alison, Christine has no doubt that her moether would have wanted to try it. “If you told her that cutting off her left arm would improve her lung function, she’d probably do it.” What does she think about the possibility that Crispr could provide a once-off fix for CF for life? “That would be amazing. Having first-hand experience, it would, literally, change lives.”

LUCINDA’S STORY: ‘We have had it for four generations’

Lucinda McNerney (45), has had a pacemaker since she was 18 to offset the effect of a congenital heart defect she was born with called Long QT syndrome.

The syndrome, which also affects two of her three children, can lead to sudden heart failure and death, sometimes in adults unaware they have the condition.

“We didn’t know the inherited nature of it about 27 years ago, so there was not much known about it,” recalled Lucinda, who was diagnosed after suffering an “event” from which she recovered. “I just got on with my life, went to college.”

For some with LQT, and this includes Lucinda’s family, LQT is particularly dangerous as it lurks in the background without any symptoms showing, until the condition is triggered with potentially fatal consequences. The trigger can be anything from heavy exercise to medications, and can affect all age groups.

Lucinda is anxious to make the world as normal and safe as possible for her two children with LQT. This involves having a defibrillator installed in the home in Cork and listening carefully to medical advice. She is the patient representative on the Sudden Adult Death council, which is run along with the Irish Heart Foundation.

Her eldest child, Oisin, has the gene, and he is being treated with beta blockers. For him, it meant that he had to give up playing competitive sports with friends.

“He [Oisin] could play a game of hurling,” said Lucinda, who is from Cork, “but the training would be so intense with your peers. Would a 10 or 11-year old stop because he felt faint? That would be the worry. It wasn’t worth the risk.”

Lucinda’s youngest child, Dervla (7), was diagnosed with LQT syndrome shortly after her birth. “She was born in Cork and brought by ambulance to Crumlin, where she was put on beta blockers,” said Lucinda. It meant that Lucinda, her mother (63), and two of her three children, plus some of her siblings had LQT.

Lucinda heard about research using Crispr technology to tackle LQT being undertaken jointly by Dr Terry Prendiville, consultant paediatric cardiologist at Our Lady’s Hospital for Sick Children, Crumlin, and Prof Timothy O’Brien, based at the Remedi centre at NUI Galway. The scientists were looking for families with LQT that were willing to donate skin samples for research with the goal of correcting the heart cells that have the genetic defect that causes the syndrome, at some point in the future.

Lucinda said it was an emotional day for the entire family.

“We have had it for four generations and we have lived with it, but it would be amazing to think that you wouldn’t have that worry for the next generation,” said Lucinda. “My brother is also a gene carrier and he has two kids, one affected and one unaffected so we are going to bring them all up – again.

“We want to encourage as many people as we can to participate in it.”