A genetic disease has been cured in living, adult animals for the first time using a revolutionary genome-editing technique that can make the smallest changes to the vast database of the DNA molecule with pinpoint accuracy.
Scientists have used the genome-editing technology to cure adult laboratory mice of an inherited liver disease by correcting a single “letter” of the genetic alphabet which had been mutated in a vital gene involved in liver metabolism.
A similar mutation in the same gene causes the equivalent inherited liver disease in humans – and the successful repair of the genetic defect in laboratory mice raises hopes that the first clinical trials on patients could begin within a few years, scientists said.
The success is the latest achievement in the field of genome editing. This has been transformed by the discovery of Crispr, a technology that allows scientists to make almost any DNA changes at precisely defined points on the chromosomes of animals or plants. Crispr – pronounced “crisper” – was initially discovered in 1987 as an immune defence used by bacteria against invading viruses. Its powerful genome-editing potential in higher animals, including humans, was only fully realised in 2012 and 2013 when scientists showed that it can be combined with a DNA-sniping enzyme called Cas9 and used to edit the human genome.
Since then there has been an explosion of interest in the technology because it is such a simple method of changing the individual letters of the human genome – the 3 billion “base pairs” of the DNA molecule – with an accuracy equivalent to correcting a single misspelt word in a 23-volume encyclopaedia.
In the latest study, scientists at the Massachusetts Institute of Technology (MIT) used Crispr to locate and correct the single mutated DNA base pair in a liver gene known as LAH, which can lead to a fatal build-up of the amino acid tyrosine in humans and has to be treated with drugs and a special diet.
The researchers effectively cured mice suffering from the disease by altering the genetic make-up of about a third of their liver cells using the Crispr technique, which was delivered by high-pressure intravenous injections.
“We basically showed you could use the Crispr system in an animal to cure a genetic disease, and the one we picked was a disease in the liver which is very similar to one found in humans,” said Professor Daniel Anderson of MIT, who led the study.
“The disease is caused by a single point mutation and we showed that the Crispr system can be delivered in an adult animal and result in a cure. We think it’s an important proof of principle that this technology can be applied to animals to cure disease,” Professor Anderson told The Independent. “The fundamental advantage is that you are repairing the defect, you are actually correcting the DNA itself,” he said. “What is exciting about this approach is that we can actually correct a defective gene in a living adult animal.”
Jennifer Doudna, of the University of California, Berkeley, who was one of the co-discoverers of the Crispr technique, said Professor Anderson’s study is a “fantastic advance” because it demonstrates that it is possible to cure adult animals living with a genetic disorder.
“Obviously there would be numerous hurdles before such an approach could be used in people, but the simplicity of the approach, and the fact that it worked, really are very exciting,” Professor Doudna said.
“I think there will be a lot of progress made in the coming one to two years in using this approach for therapeutics and other real-world applications,” she added.
Delivering Crispr safely and efficiently to affected human cells is seen as one of the biggest obstacles to its widespread use in medicine.
Feng Zhang, of the Broad Institute at MIT, said that high-pressure injections are probably too dangerous to be used clinically, which is why he is working on ways of using Crispr to correct genetic faults in human patients with the help of adeno-associated viruses, which are known to be harmless.
Other researchers are also working on viruses to carry the Crispr technology to diseased cells – similar viral delivery of genes has already had limited success in conventional gene therapy.
Dr Zhang said that Crispr can also be used to create better experimental models of human diseases by altering the genomes of experimental animals as well as human cells growing in the laboratory.
Professor Craig Mello of the University of Massachusetts Medical School said that delivering Crispr to the cells of the human brain and other vital organs will be difficult. “Crispr therapies will no doubt be limited for the foreseeable future,” he said.