Could science finally be able to cure genetic diseases?

New research has revealed that one of the major problems facing modern medicine is the treatment of crippling hereditary diseases. The introduction of CRISPR technology and advances in genetic research over the past ten years have given new hope to patients and their families, but the safety of these new techniques is still a major concern.

The results of the study are published in the journal Scientific progress.

A team of biologists at the University of California, San Diego, including postdoctoral researcher Sitara Roy, expert Annabel Guichard and professor Ethan Bier, have described a new, safer method that could one day be used to correct genetic defects. Their approach, which uses the body’s built-in DNA repair mechanisms, lays the groundwork for cutting-edge gene therapy approaches that have the potential to treat a wide range of genetic diseases.

“The healthy variant can be used by the cell’s repair machinery to correct the defective mutation after cutting out the mutant DNA,” said Guichard, senior author of the study, “Remarkably, this can be achieved even more efficiently by a simple harmless hit. “

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Working on fruit flies, the researchers engineered mutants allowing the visualization of such “homologous chromosomal template repair,” or HTR, through the production of pigments in their eyes. Such mutants originally had completely white eyes. But when the same flies expressed CRISPR components (guide RNA plus Cas9), they showed large red spots across their eyes, a sign that the cell’s DNA repair machinery had been able to reverse the mutation using the functional DNA from the other chromosome.

They then tested their new system with Cas9 variants known as “none” that target only one strand of DNA instead of both. Surprisingly, the authors found that such cuts also resulted in a high level of restoration of red eye color almost on par with normal (unmutated) healthy flies. They found a 50-70% repair success rate with the nickase compared to only 20-30% with double-stranded Cas9, which also generates frequent mutations and targets other sites throughout the genome (so-called off-target mutations). “I couldn’t believe how well nickase worked – it was completely unexpected,” said Roy, the study’s lead author. The versatility of the new system could serve as a model for fixing genetic mutations in mammals, the researchers note.

“We don’t yet know how this process will translate into human cells and whether we can apply it to any gene,” Guichard said. “Some adjustments may be needed to obtain an effective HTR for disease-causing mutations carried by human chromosomes.”

The new research extends the group’s previous achievements in precision editing with “allelic drives,” which extend the principles of gene drives with a guide RNA that directs the CRISPR system to cut out unwanted variants of a gene and replace them with a preferred version of a gene.

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A key feature of the team’s research is that their nickase-based system causes far fewer on- and off-target mutations than is known to occur with more traditional Cas9-based CRISPR edits. They also say that a slow, continuous supply of nickase components over several days may prove more beneficial than timely supplies.

“Another notable advantage of this approach is its simplicity,” Bier said. “It relies on very few components and the DNA nicks are ‘soft’, unlike Cas9, which produces complete DNA breaks, often accompanied by mutations.”

“If the frequency of such events can be increased either by promoting interhomologous pairing or by optimizing nick-specific repair processes, such strategies could be used to correct multiple dominant or trans-heterozygous disease-causing mutations,” said Roy.

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