World-first CRISPR therapy could 'transform' treatment for rare genetic diseases, but key challenges lie ahead

It has been described as a revolutionary technology — and won its inventors a Nobel Prize.

CRISPR gene editing, often simply dubbed CRISPR, is a tool that allows scientists to precisely target and modify the human genome, making it possible to correct mutations and potentially treat genetic causes of disease.

Earlier this month, scientists used CRISPR technology to achieve a significant milestone: rewrite the DNA of a baby with a rare genetic disease.

The patient, a now-10-month-old boy named KJ, is the first person in the world to successfully receive a personalised gene-editing therapy.

The landmark case, led by scientists and doctors at the University of Pennsylvania and the Children's Hospital of Philadelphia, was published in the New England Journal of Medicine.

Not long after he was born, KJ was diagnosed with a rare, life-threatening genetic disorder called CPS1 deficiency, which affects just one in 1.3 million babies.

The disorder is caused by a mutation in a gene that affects a person's ability to properly metabolise protein, and results in toxic levels of ammonia building up in the body.

Unlike other CRISPR treatments, which were designed to be used in multiple people with the same disorder, KJ's therapy was customised to correct his specific disease-causing mutation.

"This is a significant advance in our ability to modify human genes," said haematologist and gene therapy researcher John Rasko, who was not involved in the study.

While it is too early to know whether the CRISPR treatment will work long-term, researchers say it could provide a blueprint for developing customised gene-editing therapies for others with rare diseases.

"While KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient's needs," said lead researcher Rebecca Ahrens-Nicklas from the Children's Hospital of Philadelphia.

The science of rewriting KJ's DNA

The high levels of ammonia caused by KJ's CPS1 deficiency can cause severe damage to the brain and liver and even prove to be fatal.

The best available treatment for the condition is a liver transplant, but only about half of babies with CPS1 deficiency live long enough to receive one.

Scientists at the University of Pennsylvania had been investigating gene-editing therapies for similar genetic disorders and when KJ was diagnosed, they quickly mobilised to create a treatment to fix his specific mutation.

To do this, they used a "genetic engineering trick" called CRISPR base editing, a second-generation CRISPR tool, said Marco Herold, head of the Blood Cancer and Immunotherapy Lab at the Olivia Newton-John Cancer Research Institute.

"The researchers identified through [genome] sequencing that this mutation was the result of a change in DNA bases," Professor Herold, who was not involved in the study, told The Health Report.

DNA sequences are made up of four different "letters" that represent different chemical bases. The order of these letters, or bases, determines the genetic information carried in the DNA.

"[CRISPR technology] scans the DNA and runs over all the letters until it encounters the wrong letter — it can be programmed to find this," Professor Herold said.

Unlike traditional CRISPR medicines, which bind to the target DNA, cut it and silence or repair a problematic gene, base editors convert target DNA from one letter into another.

"In this case, the letter was an A and it had to be changed into a G … and that leads to the repair," said Professor Herold, whose own research focused on CRISPR screening and editing.

KJ, who had been on a highly restrictive diet since birth, as well as medication to remove ammonia from his blood, was given a small first dose of the novel gene-editing therapy at seven months of age. Over the next two months, he received two more infusions at higher levels.

Since the treatment, he has been able to eat a full-protein diet and take just half his usual medication — a sign the therapy has, at least partially, reversed his disease.

"While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising," Dr Ahrens-Nicklas said.

Professor Rasko, chair of the federal government's advisory committee on gene technology, said the speed at which the drug was developed was "extraordinary". But he stressed that longer follow-up was needed to assess its safety and efficacy and to determine whether additional doses would be necessary.

"These are very early days," Professor Rasko said.

"Everything is looking great, but let's wait a year and see what's going on."

A pathway for new gene-editing therapies

It is estimated there are more than 5,000 genetic diseases, which, while rare individually, affect hundreds of millions of people worldwide.

In Australia, around 2 million people — or 8 per cent of the population — live with a rare disease, 80 per cent of which have a genetic cause.

But the lack of economic incentive for pharmaceutical companies to develop drugs for extremely rare conditions has led to a scarcity of effective treatments, Professor Rasko said.

"Of the 5,000-plus rare genetic diseases, we have a treatment that's specific for less than 5 per cent," he said.

Peter Marks, who until recently was responsible for overseeing gene-therapy regulation at the US Food and Drug Administration, described KJ's therapy as potentially "transformational" for the treatment of rare genetic diseases.

"Although not all rare diseases may be eligible for a gene-editing approach … there could be hundreds to thousands of diseases that could be treated through an approach similar to the one described," he wrote in an editorial for the New England Journal of Medicine.

While KJ's treatment was targeted to his specific mutation, Dr Marks said the same technology could be adapted and "customised" to correct other rare genetic mutations, reducing the cost and complexity of developing new drugs.

Professor Herold agreed that the same approach could be taken to treat other illnesses caused by a single mutation, with only the CRISPR instructions needing to be changed.

"But if you have multiple mutations … there are a lot of diseases that are made up of four, five, six different mutations, then it becomes difficult," he said.

"We are not there yet, but we're working at this."

Key challenges lie ahead

Despite the promising results seen in KJ's case, there are several key challenges that need to be addressed before personalised gene editing could be scaled up and expanded.

For one, developing treatments that can successfully reach parts of the body other than the liver — where KJ's mutation occurred — is more difficult and will require further research.

"Because the liver is like a big sieve that processes poisons, toxins and manufactures hormones and other proteins … the lipid nanoparticles [which encase the gene-editing products] get taken up there," Professor Rasko said.

Even though KJ's treatment was a "breathtakingly impressive" proof of concept, replicating and adapting it for other patients would still be resource-intensive, he added.

"Every time we do this, we have to alter the guide DNA and the technology has to change. It has to be quality-controlled, it has to pass some form of regulatory approval … it's not just a one-size-fits-all."

A more established therapeutic approach called gene addition therapy, which involves introducing a working copy of a gene (rather than correcting one), had been a "scientific and medical success" but "an economic failure" to date, Professor Rasko said.

"Companies that have been valued at billions of dollars have had to walk away because they can't recoup their costs without charging millions of dollars a pop for these genetic therapies," he said.

But, he said, the rate of development and innovation in the field of gene editing — which may help to solve some of the challenges — was "awesome".

"You just can't keep up."

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