Tak­ing a pair of scis­sors to our DNA

How new gene-edit­ing tech­nol­ogy is set to rev­o­lu­tionise the fight against dis­ease

The Irish Times - Tuesday - Health - - Health l Gene Technology - Sean Duke

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.

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.”

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.”

‘‘ 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.

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