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CRISPR Technique Could ‘Turn Off’ Muscular Dystrophy Gene, Study Says

The corrected DNA could be inherited by subsequent generations of cells.

by Melissa Cronin
Nov 13 2015, 10:00am

Image: Shutterstock

Everything we are comes down to our genes, those basic chunks of DNA that hold the information for every beautiful detail about us. Unfortunately, those same genes also hold the coded instructions for something more ugly: disease. But what if we could change our genes to prevent a disease from ever rearing its head?

A recent paper published in the journal Molecular Therapy found that, at least for one disease, that may be possible very soon. According to lead researcher Peter Jones, of the University of Massachusetts Medical School, a newly-discovered technique could prove the key to "potentially a permanent cure" for a debilitating form of muscular dystrophy.

A breakthrough gene-editing technique that has swept through the medical world, CRISPR/Cas9, has quickly become the newest darling of genetics researchers. Scientists are churning out hundreds of papers on the technique, marveling at its ability to defy the laws of inheritance that have limited scientists' study of genetics for centuries. Now, with a slight modification, the technique has been applied to a disease called Facioscapulohumeral Muscular Dystrophy (FSHD)—and with surprising results.

FSHD is a genetic disorder that affects the muscles of the face, shoulder blades and upper arms. The wasting disease usually rears its head fully around age 20, though sometimes as early as infancy. It's the third most-common genetic disease of skeletal muscle, with some estimates putting its prevalence at one in 8,000 children. The symptoms vary by case, but about one-fifth of patients diagnosed with FSHD wind up having to use a wheelchair to get around.

For a long time, there was no cure, and not even a treatment, for FSHD.

The disease essentially comes down to a mutation on one single gene, called that DUX4 gene, that that triggers its expression. Unfortunately, it's very tricky to isolate DUX4. The gene is located within a larger chunk of DNA, a section called D4Z4—and there are hundreds of identical copies of this D4Z4 section, on multiple chromosomes in the cell. That means that there are hundreds of places where the pathogenic gene could be located.

But luckily for researchers hoping to prevent the disease, just one of these duplicate sections actually expresses the pathogenic gene that causes FSHD. That section is located on chromosome 4 (remember, most people have 23 pairs of chromosomes in each cell).

Essentially, changing the genetic basis for the disease could foreseeably wipe it out entirely

In layman's terms, there are lots of places for the gene that causes FSHD to be hiding. But there's only one particular spot on the chromosome that needs to be fixed in order to prevent the disease. So, the question became: can you isolate that specific unit of DNA and prevent it from expressing the pathogenic copy of the DUX4 gene?

Here's where CRISPR, the newest wunderkind of genetic tools, comes in.

CRISPR is basically a gene that, with the help of the protein that enables it, called Cas9, as well as a guide RNA that tells it where to go in the genome, can be used as a microscopic engineering tool to snip out bits of DNA and neatly tie the strand back together again. In the past few years, the gene-editing technique has garnered heaps of attention, with some scientists even going so far as to call it a "gene-editing revolution." In short, the CRISPR-Cas9 technique can change a person's very DNA —a technique that could signal a breakthrough for the way we treated genetic diseases.

"Rapid advances in genome-editing platforms are actively underway, and will hopefully lead to more effective and specific correction of many diseases," Jones told Motherboard, adding that he and his team took a slightly non-traditional approach to using CRISPR.

Usually, CRISPR is a cutting machine, hacking away at pathogenic genes. But sending a weed-whacker into a delicate genome to cut away hundreds of spots is risky, and could result in mistakes. There is, however, a way to leave genes intact, but also make sure that they stop function: when you have a problem gene, simply switching it off can be just as effective as removing it.

This time around, scientists used a "non-cutting" version of the protein Cas9, called dCas9. They fused this to a protein whose function is to switch the expression of genes to the "OFF" position, essentially rendering their function moot. Only one of these genes is actually responsible for the expression of the pathogenic gene. But with all of the genes that could possibly express it switched off, that one single gene that leads to FSHD is guaranteed to be off, as well.

Besides preventing the expression of the disease itself, this method comes with an added bonus: by changing that actual, physical structure of the genome, the corrected DNA could be inherited by subsequent generations of cells. Essentially, changing the genetic basis for the disease could foreseeably wipe it out entirely.

CRISPR, however, isn't without its detractors. A debate has erupted around the technique, which has been around for about three years. CRISPR is still relatively new, and some scientists have concerns about the unseen consequences its use may have, particular as research turns toward human embryos.

Already during a study in China on human embryos, safety concerns were raised after a surprising number of accidental, potentially harmful mutations were likely created by the use of CRISPR/Cas9 on the genome.

There's also a robust debate about whether the technology will be harnessed to create "designer babies," children who are genetically modified for desired traits, like intelligence, looks, athleticism, and so on. More than one critic has noted that it's a slippery slope between choosing desirable traits for babies and eugenics. A coalition of scientists has even called for a moratorium on research concerning human genome modification using CRISPR.

Visual overview of the CRISPR/dCas9 process used to turn off the pathogenic gene that causes FSHD. Image: Peter Jones et al

For now, while research continues, many scientists are hopeful that CRISPR will become a powerful tool in fighting diseases, despite its obstacles. Jones, the FSHD author, certainly is optimistic about his team's findings.

"Our work has demonstrated that, in principle, such a strategy is feasible for FSHD, by showing that the CRISPR system can be used to target and correct a very unusual part of the human genome," Jones said, adding that rapid advances in technology could make this type of approach a viable one for many diseases.

CRISPR has already been tested as a potential way to stop HIV infection in human cells, prevent cancer cells from multiplying, and reverse mutations that cause blindness. Soon enough, we may be able to add curing muscular dystrophy to that list.