Duchenne Muscular Dystrophy (DMD) was first documented in the 1860s. More than a hundred years later, researchers discovered the genetic mutation underlying the progressive muscle degeneration that defines this disorder. Despite further studies into the mechanism of DMD, no effective treatment currently exists. Like many rare genetic diseases, DMD ultimately results in loss of quality of life and death. But thanks to advances in gene editing technology, that could soon change.

“With technologies like CRISPR, having a genetic diagnosis can lead to innovative ideas that weren’t possible in the past,” explains Monkol Lek, PhD, assistant professor of genetics at Yale School of Medicine. For the past few years, Lek has been collaborating with leaders in academia and industry to create a new treatment for DMD. If successful, the project would be a massive breakthrough not just by virtue of treating the disease, but in how it does so. Lek and his collaborators are aiming to carry out one of the first ever CRISPR clinical trials. Lek and his collaborators have completed the important pre-Investigational New Drug (pre-IND) Application meeting with regulators from the Food and Drug Administration and this year plan to conduct further safety and efficacy studies.

CRISPR refers to a powerful gene-editing technology that has garnered widespread excitement in recent years. Its potential role in therapies is of particular interest because it can directly address the genetic basis of a disease. In the case of DMD, the mutation occurs in the gene responsible for producing a protein called dystrophin. Lek explains that the current standard of treatment for DMD is a prescription of steroids, but this fails to address the underlying issue. “Surely we can do better than that,” he says. “The thought is: how do we bring genetics into treatment? Not every mutation is the same.”

The application of CRISPR reflects a growing movement to engineer individualized therapies. Researchers now have the capacity to isolate the specific mutations and putative mechanisms of rare disease. In this “N-of-one,” approach, a study is designed around a single patient. In the case of Lek’s pursuit, that patient is Terry Horgan.

Terry’s parents, grandparents, and great-grandparents were all too familiar with DMD. By the time Terry was diagnosed, they’d already watched as their sons, brothers, and uncles lost their mobility—and eventually their lives—to this rare disease. For over 25 years, Terry has bravely fought against the disease in hopes of receiving a treatment to pause or reverse the condition. Despite the difficult diagnosis, Terry enjoys playing a variety of video games and spending time with family and his service dog, Mischief. Professionally, Terry works at Cornell University as an Administrative Assistant in the Information Science department. Lek learned about Terry through his brother, Rich Horgan. Rich founded an organization called Cure Rare Disease, which seeks to develop customized therapeutics for individuals with rare, genetic diseases. While they were speaking together at a conference in 2018, Lek asked Rich about his brother’s mutation. Their conversation helped ignite a collaboration that has spanned the years since. Lek — along with Angela Lek, Associate Research Scientist at Yale Medical School — joined Rich’s organization and the effort to craft a treatment for Terry. The husband-wife team set to work immediately and haven’t looked back since.

Terry has a deletion in exon 1, which affects the muscle-specific type of the DMD gene. But the DMD gene has two other “types” that could - potentially - be turned on instead. Lek explains that their goal is to switch on one of these types, the cortical isoform, within skeletal muscle cells, as a means of compensating for the mutation in exon 1. RNA sequencing showed that Terry’s muscle already exhibits a slight compensatory response, suggesting that this mechanism is in place and may simply need a boost. Studies on other genetic disorders provide further support for this idea. Individuals with X-linked dilated cardiomyopathy also lack exon 1 deletions, but thanks to adequate expression of the cortical isoform, they don’t show the DMD phenotype.

Though this treatment is specific to Terry, it could change the medical landscape for anyone with DMD. “N-of-one clinical trials could be a way of building a safety profile for new experimental drugs,” Lek says. “One way you avoid making the same mistakes is to share data.” By making the results available to other researchers, Lek says that subsequent gene therapy efforts don’t need to start from scratch.

Lek wants to augment a new standard of data sharing because he understands the frustration and fear of waiting for a cure. Shortly after graduating college, he was diagnosed with muscular dystrophy. He says that he knows “what it’s like to feel like you’re wasting away.” Lek’s personal experience with a rare disease imbues his work with urgency. Since it relies on results from patients in clinical trials, designing translational therapies poses significant risk. But Lek sees no other option. “I’m willing to take this risk, because, as a patient, I’m not willing to sit around and do nothing.”

Translational research challenges the traditional way of thinking that people learn from basic research, Lek says. In his work on DMD, he describes his focus as “treat first, publication second”. “All the decisions we’re making have to do with how we can translate our results to a clinic. We’re less concerned with high-impact publications,” he says. Though Lek sees as an abundance of work on model systems, he feels there is too little emphasis on translating results into impactful treatments. “We’re here to turn research into realities. Developing individualized therapies for rare disease patients is at the forefront of our lab’s mission", Lek says.

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