The promise of new CRISPR gene-editing technology has always been that it might lead to a cure for specific genetic diseases. Recently published findings from a team of researchers at the University of Massachusetts Medical School in Worcester, Mass., suggest that a modified form of this CRISPR gene-editing technology may eventually result in a cure for facioscapulohumeral muscular dystrophy (FSHD), a form of the disease that leads to progressive muscular degeneration in the face, shoulder blades and upper arms.
The new CRISPR technique works by silencing the gene (DUX4) thought to be responsible for the genetic disease. Once you “turn off” the gene, it can no longer encode for the toxic proteins that lead to the deterioration of human skeletal muscle.
Unlike other CRISPR techniques that focus on editing a troublesome gene, this modified approach focuses on repressing the gene. As Dr. Charis Himeda of the University of Massachusetts Medical School told me in a conversation, this technique is a “non-cutting version of CRISPR” that involves the dCas9 protein rather than the Cas9 protein. The difference between “Cas9” and “dCas9” may sound like a case of arcane biological semantics for non-scientists, but the implications are actually quite important, says Dr. Himeda.
That’s because researchers are not actually “editing” the gene, they are simply turning off something that should have been repressed in the first place. It turns out that DUX4 appears quite frequently as part of a repetitive DNA sequence known as D4Z4. In most cases, the size of the D4Z4 repeat is long enough that the gene is properly repressed. If the D4Z4 repeat is not long enough, however, the DUX4 gene is not repressed – and that’s what causes all the problems for the estimated 870,000 patients worldwide who suffer from FSHD.
Bottom line: if the human body is not repressing a gene by itself, there needs to be a way to go in manually and switch it off. That’s the power of CRISPR.
There are several reasons why the research being carried out by the University of Massachusetts Medical School is especially promising. This is the first study to show that the repeat genome can be effectively targeted using CRISPR technology, the first use of CRISPR inhibition for a human disease, and the first use of CRISPR technology in primary human muscle cells.
In the article describing the work in Molecular Therapy, co-authors Charis Himeda, Takako Jones and Peter Jones highlight the important implications for similar types of genetic diseases: “With increasing evidence that the repeat genome (comprising nearly half the human genome) plays important roles in gene regulation, additional diseases will likely be found associated with aberrant repetitive genomic sequences,” they write. “We have provided the first evidence that the repeat genome can be targeted via the CRISPR system, which is likely to prove useful as this hitherto overlooked portion of the genome is decoded.”
While the promise of finding a treatment for any genetic disease is certainly a plus, there are obvious reasons for caution with any “cutting” version of the CRISPR technique. Anytime people hear about cutting and snipping DNA, people are going to be concerned, even if you’re potentially discovering a cure for a disease. That’s why the researchers focused on the “non-cutting” version. As Dr. Himeda explained to me, “Cutting a repeat sequence that is present in hundreds of nearly identical copies could be very dangerous or even catastrophic for a cell.”
Ultimately, that’s an issue that any of the new era of genome-editing companies – among them Editas Medicine, Sangamo Biosciences, Intellia Therapeutics and CRISPR Therapeutics — must confront as they search for cures. Anytime you’re altering gene expression in humans, there’s a risk that something might go wrong in a completely unexpected way.
Yet, investors do not seem to be dissuaded. In August, a group of investors led by Fidelity Investments and a fund backed by Bill Gates poured $120 million into Editas Medicine, the Cambridge-based biotech start-up that is using CRISPR techniques to develop cures for more than 5,000 different genetic diseases. Since its launch in November 2013, Editas has been licensing genome-editing technologies from researchers at Harvard, Massachusetts General Hospital, and the Broad Institute of MIT.
For now, the University of Massachusetts Medical School researchers plan to concentrate on continued basic scientific research to further refine their modified CRISPR technique. Any plans for clinical trials are “years away” at best. While Dr. Himeda says she hasn’t yet given it serious consideration, it’s possible to imagine a theoretical scenario in which a company such as Editas Medicine licenses CRISPR technologies to develop a medical cure for FSHD.
Going forward, it’s easy to see how greater knowledge of the human genome – knowing which gene does what as well as its precise location within the genome – has enormous potential. While CRISPR was once just a lab technique a few years ago, there now exists growing hope that further CRISPR innovation will eventually lead to treatments for a growing number of genetic diseases where researchers have pinpointed exactly which gene (or genes) is causing the problem.