Genome-editing tool offers hope for intractable genetic diseases

Scientists have developed a genome editing method that could one day be used to treat conditions such as progeria and Huntington's disease.

In a study published in Cell Research, the authors described a tool named SATI, a variation of the CRISPR approach to genome editing. Compared with its predecessors, SATI allows alteration of a wider array of mutations in more cell-types. It opens up the possibility of treating genetic conditions that were previously thought intractable.

'This study has shown that SATI is a powerful tool for genome editing,' said Professor Juan Carlos Izpisua Belmonte at the Salk Institute in La Jolla, California, lead study author. 'It could prove instrumental in developing effective strategies for target-gene replacement of many different types of mutations, and opens the door for using genome-editing tools to possibly cure a broad range of genetic diseases.'

SATI is a gene 'knock-in' method – meaning that it works by inserting a normal copy of a mutated gene in the noncoding DNA before the site of the problem gene. This means that the new gene can produce the functional proteins the cell needs alongside the mutated gene and that it can relieve symptoms without needing to fully replace a problematic gene.

To test the effectiveness of SATI, the researchers studied mice harbouring a mutation in the LMNA gene that leads to a premature ageing syndrome called progeria in mice and humans alike. They injected newborn mice with a healthy portion of the gene, which replaced the faulty counterpart by taking advantage of DNA repair machinery found within cells.

The treated mice not only had an increased lifespan, but also showed an improvement in overall health and body function. The researchers found very few instances of off-target effects in unintended parts of the genome, which are a concern when using genome editing inside the body. An improvement of symptoms was also seen when SATI was performed in adult mice with progeria. The researchers believe that this highlights the utility of the technique, as many genetic diseases are diagnosed later in life.

In contrast to previous methods, SATI was able to edit the genes within both dividing and non-dividing cells with a similar efficiency as it is able to use a variety of DNA repair machineries.

Although the mice showed an improvement in symptoms of progeria, only small and sometimes undetectable populations of cells were successfully edited by the SATI. The researchers now aim to hone the technique to increase its efficiency.

'Specifically, we will investigate the details of the cellular systems involved in DNA repair to refine the SATI technology even further for better DNA correction,' said Dr Reyna Hernandez-Benitez, also at Salk, and co-first author on the paper.