Geneticists Show How to Alter Disease DNA Without Creating Mutations

Scientists have found a new use for a precision gene-editing technique that could prove safer and treat disease without creating mutated side-effects.

With the CRISPR-Cas9 technology that enables researchers to remove, add or alter sections of a DNA sequence, the prevalence of genetic diseases might be reduced in future generations.

Scientists at the Salk Institute for Biological Studies in La Jolla, California outlined in their research in a paper published Thursday in the journal Cell.

CRISPR is poised to be one of the most important — and most profitable — biology discoveries in our lifetime, though the high hopes of scientists have not quite panned out yet.

With the technology, scientists can edit DNA more cheaply and precisely than ever before, snipping out specific segments of a DNA sequence and replacing them with new sequences. This presents possibilities that include eliminating genetic disease, reverse-engineering dinosaurs, and even altering human embryos.

A new study could improve scientists’ chances of treating genetic diseases.

Scientists used CRISPR-Cas9 to alter gene expression in mice to treat mouse models of human diseases without creating double-strand breaks in DNA that could cause unexpected harmful mutations. In other words, they changed the activity of DNA instead of changing the sequence of DNA. The changes in gene expression, they report, improved the condition of mice with human diseases: type I diabetes, acute kidney injury, and muscular dystrophy.

This research is promising because it offers the possibility that scientists can wield CRISPR, a technique with lots of potential for cheap and effective genetic therapies, without worrying as much about creating unintended consequences in people, plants, or animals they’re treating.

“Cutting DNA opens the door to introducing new mutations,” senior author Juan Carlos Izpisua Belmonte, a gene expression researcher at the Salk Institute for Biological Studies, in a statement. “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.”

By altering gene expression in the subject mice’s DNA, scientists saw significant improvement in the human diseases that the mice were modeling. This is a small but significant step forward for CRISPR-Cas9, which many have loudly touted as the future even as it has not quite delivered on that promise.

This paper comes with the caveat, of course, that the scientists conducted the research on mice, so testing on human subjects is probably still years off. But this study proves that CRISPR-Cas9 can be used to alter gene expression, which is a very real development in that it moves the ball forward in helping treat diseases in humans.

Abstract:

Current genome-editing systems generally rely on the creation of DNA double-strand breaks (DSBs).This may limit their utility in clinical therapies, as un-wanted mutations caused by DSBs can have deleterious effects. The CRISPR/Cas9 system has recently been repurposed to enable target gene activation,allowing regulation of endogenous gene expression without creating DSBs. However,i n vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guideRNAs. As proof-of-concept, we used this technology to treat several mouse models of human diseases.Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo,leading to observable phenotypic changes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases.