Mouse CRISPR

An adapted CRISPR technique could be used to treat incurable diseases, such as diabetes and muscular dystrophy. 

The traditional method of using the gene editing technique snips DNA in specific locations to delete faulty genes or over-write flaws in the genetic code. Instead, the updated form “turns up the volume” on selected genes. 

This holds the potential to overcome the problem of the wrong genes being modified by mistake, which are often referred to as off-target effects, and are largely viewed as a huge safety barrier to using CRISPR in a clinical context. 

Juan Carlos Izpisua Belmonte led the work at the Salk Institute in La Jolla, California. He explained, “Cutting DNA opens the door to introducing new mutations. That is something that is going to stay with us with CRISPR ot 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.”

Although a CRISPR-style guide is still in use, the difference is that the Cas9 enzyme latches onto the genome, rather than cutting it at the site of interest. In addition, it includes a third element, consisting of a molecule that homes in on the Cas9 and switches on whatever gene it is attached to. 

A paper, published in Cell, highlights how this technique could potentially be applied to a range of illnesses. In a study, a team managed to prove that mice, with a version of muscular dystophy, a fatal muscle wasting disorder, recovered muscle growth and strength. 

The illness itself is caused by a mutation in the gene that produces dystrophin, a protein found in muscle fibres. Instead of trying to replace the gene with a healthy one, the team increased the activity of a second gene that produces a protein called utrophin that is very similar to dystrophin and can compensate for its absence. 

Belmonte added, “We are not fixing the gene, the mutation is still there. 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.”

Similarly, the team went on to show that normal kidney function could be restored in animals with a genetic kidney disorder. As well as this, they were able to induce some liver cells to turn into cells that resembled beta cells, the pancreatic cells that produce insulin, to improve the symptoms of mice with diabetes. 

Although the work is a great achievement, further refinement and safety testing will need to take place before it can move into patient studies. 

Providing an alternative standpoint is Professor Doug Melton, a scientist from Harvard who is working to develop lab-grown pancreatic cells. He believes that steering a liver cell towards making insulin would not necessarily have advantages over insulin injections, because it would not restore the body’s ability to regulate blood sugar. 

He said, “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. 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, suggested that a potential drawback of the work was that the target genes would be boosted in organs throughout the body, in turn raising the possibility of off-target effects. 

However, Belmonte is continuing to raise awareness of his work, adding that the technique may even have the potential to reverse the effects of old age in the future. 

“Our goal will be to re-activate genes silenced by ageing, or to use the system to replenish stores of adult stem cells, which promote regeneration but are typically depleted with age.”