Incurable diseases such as diabetes and muscular dystrophy could be treated in future using a new form of genetic engineering designed to boost gene activity, according to scientists.
The technique is an adapted version of the powerful gene editing tool called Crispr. While the original version of Crispr snips DNA in precise locations to delete faulty genes or over-write flaws in the genetic code, the modified form “turns up the volume” on selected genes.
This potentially overcomes the problem of the wrong genes being modified by mistake, so-called off-target effects, which is viewed as a major safety barrier to using Crispr in a clinical context.
“Cutting DNA opens the door to introducing new mutations,” said Juan Carlos Izpisua Belmonte, who led the latest work at the Salk Institute in La Jolla, California. “That is something that is going to stay with us with Crispr or any other tool we develop that cuts DNA. It is a major bottleneck in the field of genetics – the possibility that the cell after the DNA is cut may introduce harmful mistakes.”
Crispr has been a game-changer in biomedical research because of the ease and accuracy with which it can be used to edit the genetic code. Crispr is a guide molecule made of RNA that allows a specific site on the genome to be targeted. It is normally used along with a bacterial enzyme, called Cas9, which acts as molecular scissors, chopping the DNA at the exact point required.
In the new version a Crispr-style guide is still used, but instead of cutting the genome at the site of interest, the Cas9 enzyme latches onto it. The new package also includes a third element: a molecule that homes in on the Cas9 and switches on whatever gene it is attached to.
The new paper, published in Cell, demonstrates how this strategy might be applied to a range of devastating illnesses.
The team showed that mice, with a version of muscular dystrophy, a fatal muscle-wasting disorder, recovered muscle growth and strength. The illness is caused by a mutation in the gene that produces dystrophin, a protein found in muscle fibers. However, rather than trying to replace this gene with a healthy version, the team boosted the activity of a second gene that produces a protein called utrophin that is very similar to dystrophin and can compensate for its absence.
“We are not fixing the gene, the mutation is still there,” said Belmonte. “Instead ... the mice recover the expression of other genes in the same pathway. That is enough to recover the muscle function of these mutant mice.”
In another mouse experiment, the team showed that normal kidney function could be restored in animals with a genetic kidney disorder. They were also able to induce some liver cells to turn into cells that somewhat resembled beta cells, the pancreatic cells that produce insulin, to improve the symptoms of mice with diabetes.
The work is seen as an impressive technical feat but will require extensive refinement and safety testing before it can move into patient studies.
For instance, Prof Doug Melton, a Harvard scientist who is working to develop lab-grown pancreatic cells, said that steering a liver cell towards making insulin would not necessarily have advantages over insulin injections because this would not restore the body’s ability to regulate blood sugar. “The key is to make a cell that accurately responds to changing sugar levels and secretes just the right amount of insulin, as does a beta cell,” he said. “To be fair, they seem to be saying [they’ve made] beta-like cells, which is accurate, but probably not good enough for a patient.”
Alena Pance, a senior staff scientist at the UK’s Wellcome Trust Sanger Institute, said a potential drawback of the work was that the target genes would be boosted in organs throughout the body – raising the possibility of off-target effects. “These results bring hope for a targeted gene therapy and widen the application of the technology ... but these issues would need to be investigated in depth before any application in humans is considered,” she said.
Belmonte said that in future, the technique may even have the potential to reverse the ravages of old age – although this application is not on the immediate horizon. “Our goal will be to re-activate genes silenced by aging, or to use the system to replenish stores of adult stem cells, which promote regeneration but are typically depleted with age,” he said.
Brian P. McDonough, MD, FAAFPPeer
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