Hoping for a cure

CRISPR technology may hand a lifeline to patients living under the terminal cloud of Duchenne muscular dystrophy.

Microscopic image of the calf muscle of a person with Duchenne muscular dystrophy, in which muscle fibre cells have been replaced with fat cells.   Edwin P. Ewing, Jr./Wikimedia Commons  (public domain)

Microscopic image of the calf muscle of a person with Duchenne muscular dystrophy, in which muscle fibre cells have been replaced with fat cells. Edwin P. Ewing, Jr./Wikimedia Commons (public domain)


Eric Olson fondly remembers when Ben Dupree visited his laboratory, based at the University of Texas Southwestern Medical Center. Dupree, then a 24-year-old graduate from Southern Methodist University of Texas, rolled his wheelchair into Olson’s laboratory and peered with wide eyes at the photograph that could save his life. In an image of his own cells, he saw the correction of a mutation responsible for Duchenne muscular dystrophy, the terminal illness that had prevented him from being fully active since age seven.

At the time, Dupree had already lived four years past his life expectancy. He was one of many hopeful young men with muscular dystrophy who had donated his cells to Olson, co-director of the University of Texas Southwestern Wellstone Muscular Dystrophy Cooperative Research Center. Olson and his colleagues had used a specific gene editing technology, known as CRISPR, to correct the mutated gene in Dupree’s own cells. Just a few years prior, in the same laboratory, Olson and his colleagues used the same technology to cure muscular dystrophy in mice models.

 “We looked at their muscles for several months and we saw that the missing protein, called dystrophin, was restored in very high levels in their muscles,” says Olson. “That was a eureka moment when we realised we had the potential to bring a whole new technology to bear on this disease.”

According to the US Centers for Disease Control and Prevention, Duchenne muscular dystrophy is the most common fatal genetic disorder diagnosed in childhood. Duchenne affects about one in every 3,500 male births worldwide and is caused by a mutation in the gene that encodes for the protein dystrophin. The absence of dystrophin causes progressive muscle weakness, leading to serious medical problems and a life expectancy of only 20 to 30 years in most cases. Since the Duchenne gene is found on the X chromosome, the disease is most common in males. Although there are medical treatments that may help slow its progression, there is currently no cure for Duchenne. Scientists are hopeful that CRISPR can provide just that.

“CRISPR is different from every other therapy that’s been applied to muscular dystrophy,” says Olson. “All other therapies treat the symptoms of the disease, but CRISPR treats the cause of the disease by removing the molecular error in the DNA code.”

CRISPR is a bacterial defence system that allows researchers to quickly and easily edit genes. You can think of it as a pair of genetic scissors. These scissors are more efficient than other gene-editing technologies because they can be easily redirected to cut chosen spots on human chromosomes. Scientists can, for example, use the technology to snip a single gene out of the 20,000 genes in the human genome, including those causing genetic diseases. The function of the specific technology Olson is using, known as CRISPR/Cas-9, was first described in 2012 by Jennifer Doudna and Emmanuelle Charpentier, at the University of California, Berkeley. In June this year, Doudna and Charpentier were awarded a US patent for their CRISPR/Cas-9 invention. Since its discovery, CRISPR has been used in thousands of studies in the hope of finding effective treatments, or even cures, for a range of conditions and diseases, including HIV-1, blindness, mental health disorders and cancer.

CRISPR shows great potential for treating certain diseases, such as cancer, that have previously been limited by the lack of disease models, says Yan Zhang, an assistant professor of biological chemistry at the University of Michigan. “We could study and find thousands of genes that might be cancer-related, but it’s hard to knock out every single one of them and determine which one is the actual cause,” says Zhang. “But here, we can quickly engineer thousands of disease models in human cells or in mouse models and assess the impact of certain drugs.”

Likewise, CRISPR could be incredibly useful for safely treating muscular dystrophy in human patients, says Thomas Saunders, director of the Transgenic Animal Model Core at the University of Michigan. “It’s really a question of being able to take the CRISPR agents and put them into the muscles of the patients so that, unlike other types of genetic therapies, we can deliver the CRISPR protein to the muscle that will decay automatically without causing other damage,” he says.

Despite its early promise for curing muscular dystrophy, researchers have yet to use CRISPR in human trials within the United States. “We’ve demonstrated that it can work in the human genome and can effectively restore the missing protein,” says Olson. “And so, the next step is to test it in the actual patients in their bodies. That is going to require additional safety studies, further improvement of the efficiency, and appropriate regulatory approvals from the Food and Drug Administration.”

It may take a few years to get approval to test CRISPR in humans, but in the meantime Olson is working to improve the technology’s efficiency. In February last year, he founded Exonics Therapeutics, a biotechnology company based on his research, and in November secured $40 million from a science-driven capital firm, the Column Group. This funding may allow Exonics Therapeutics to be a leader in improving the efficiency of CRISPR and develop a cure or treatment that will overcome safety concerns.

The level of public interest in Olson’s work shows the extraordinary impact this technology could have in the very near future. Dupree and many other patients worldwide remain hopeful that CRISPR could help prevent or cure the 20,000 cases of Duchenne muscular dystrophy that arise every year.

“I receive emails every day from families in all countries and places on the earth with sons who have muscular dystrophy, and there’s been enormous patient enthusiasm for what we do,” says Olson. “It’s really made this a very personal quest.”

Edited by Andrew Katsis