CRISPR Modified to Epigenetically Treat Diabetes, Kidney Disease, Muscular Dystrophy

Maricruz Casares
Diciembre 8, 2017

The Salk scientists adapted the regular CRISPR mechanism to influence gene activation without actually changing the DNA itself.

"We have been able to overcome this problem", he says.

As to the mice with muscular dystrophy, the researchers stimulated the activity of genes that have previously showed that they could reverse the symptoms of this disease. But the entire protein, consisting of dCas9, the switches and the guide RNAs, is too big to fit inside one of these AAVs. They also optimized the guide RNAs to make sure all the pieces ended up at the desired place in the genome, and that the targeted gene was strongly activated.

It took a lot of experimenting with different combinations of guide RNAs and switches before Belmonte and his team landed on a two-virus setup that worked together as a team inside the cell, targeting exactly right gene and flipping the switch.

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To test this new technique, the researchers used mice in which they induced a disease severe renal, type 1 diabetes, and a form of muscular dystrophy. For muscular dystrophy, the researchers expressed genes that have been previously shown to reverse disease symptoms, including one particularly large gene that can not easily be delivered via traditional virus-mediated gene therapies. In the case of kidney disease, they activated two genes known to be involved in kidney function, and observed not only increased levels of the proteins associated with those genes, but improved kidney function following an acute injury. In the diabetic mice, the targeted genes were those that promote the growth of insulin-producing cells, and after treatment, the mice were found to have lower blood glucose levels.

But perhaps the most dramatic result was achieved with mice suffering from Duchenne muscular dystrophy, a lethal muscle-wasting disorder that can be traced back to a mutation in a single gene called dystrophin.

"We have been very satisfied with the results obtained in these mice which showed that by inducing the activation of certain genes, we can at the same time to observe physiological changes", says Fumiyuki Hatanaka, a scientist at the Salk Institute, one of the main co-authors of the study. The researchers plan to try to apply the technique to other cell types to help treat other diseases, and conduct more safety tests before human trials can begin.

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