Credit: Cure Rare Disease

Rich Horgan still remembers the day his younger brother, Terry Horgan, could no longer summon the strength to walk up the steps of a movie theater. Terry was born with Duchenne muscular dystrophy, a rare genetic disease that causes progressive muscle loss. Today, at 24, he’s too old to participate in one of the many clinical trials of experimental drugs for the rare disease. His heart strength is declining, and he doesn’t sugarcoat his situation: “It sucks, but you got to keep moving.”

Lately, however, Terry has something to hope for: a personalized gene-editing therapy that could provide a genetic workaround to the particularly rare mutation that causes his disease.

Credit: Cure Rare Disease

Two years ago, Rich started a nonprofit to fund basic research on his brother’s disease. Before long, Rich’s ambitions grew, and in the summer of 2018, he began working on a way to treat Terry. This spring, Rich’s nonprofit, Cure Rare Disease, announced the daring goal to use CRISPR gene editing to treat Terry and other individuals with rare forms of neuromuscular disease. Until recently, Terry had never even heard of CRISPR; by this time next year he could become the first recipient of a custom-designed CRISPR therapy.

Rich, who is 28 and a recent graduate of Harvard Business School, is far from the first person to devote his life to finding a cure for a family member. He’s also not the only one to launch a foundation to develop custom-designed drugs for genetic diseases. Other groups with those ambitions are focusing on older technologies—antisense oligonucleotides and viral-based gene therapy. Cure Rare Disease is the first nonprofit to spearhead the development of personalized CRISPR therapies.

In early 2018, while still a student, Rich caught wind of a Boston Children’s Hospital researcher’s effort to develop a personalized drug for a girl with a rare form of a neurodegenerative condition called Batten disease. Timothy Yu managed to design, test, and manufacture an experimental drug for Mila Makovec in just 10 months.

“That was music to my ears,” Rich says. He didn’t have a science education, but he knew that Yu was flipping the typical model of drug development, in which it can take more than a decade and billions of dollars to make a drug, on its head. It got Rich thinking, Could a similar customized drug help his brother?

That spring, Rich consulted with Yu. In fact, Rich is one of hundreds of people who have reached out to Yu for help in the past 2 years. But the kind of drug that Yu made for Mila, called an antisense oligonucleotide, works by masking an errant snippet of DNA. That approach wouldn’t work for Terry, who is missing a stretch of DNA code—namely, part of the gene for dystrophin, a protein critical for the structure and function of muscle cells.

Then at a neuromuscular disease conference in New Orleans in June 2018, Rich shared Terry’s diagnosis with the Yale School of Medicine geneticist Monkol Lek, who began a career in genetics after he was diagnosed with limb-girdle muscular dystrophy in his early 20s. Lek pored over Terry’s genome. A few days later, he came back to Rich with good news.

“I think we actually have a way to use CRISPR to directly address your brother’s mutation,” Lek recalls telling Rich. Just a few years ago, that statement would have been irresponsible, if not untrue. “We can actually say things like that now,” he adds.

Terry’s dystrophin gene is missing a chunk of DNA that starts in a region called the muscle promoter—as it sounds, necessary for turning on the production of dystrophin in muscle—and extends into a stretch of DNA called exon 1, the first of 79 protein-coding regions that our cells stitch together into instructions for manufacturing the protein. When Lek studied Terry’s DNA, he noticed that the rest of the dystrophin gene is intact. Furthermore, Terry, like the rest of us, has two alternative versions, or isoforms, of promoter and exon 1; they are normally used for making dystrophin in only certain types of brain cells. It dawned on Lek that these brain isoforms of exon 1 were like built-in backups. Terry’s cells just needed help turning that backup code on.

Lek knew just the tool for the job: a version of CRISPR called CRISPR activation, which he could program to navigate to a brain isoform of exon 1 and flip it on.

Rich asked how much it would cost. Lek said he could test the concept in the lab for about $5,000. Rich sent the funds, and by early fall, Lek had promising news: a CRISPR activation system could prompt HEK cells—a common tool in biology labs—to produce the dystrophin protein, something that they normally don’t do.

By then, Rich had already started assembling a team of respected scientists to advise and conduct different parts of a project to design a custom CRISPR activation therapy for Terry. That team includes Stanley Nelson, a bioinformatician from the University of California, Los Angeles, who studied Terry’s mutation at the DNA, RNA, and protein levels; Charles Emerson Jr., a muscular dystrophy expert at the University of Massachusetts Medical School who developed cell lines from Terry’s muscle biopsy; and Lek, whose lab has used those cell lines to test different versions of the CRISPR activation therapy that he’s designing for Terry.

Rich, meanwhile, has hired the contract research firm Charles River Laboratories to assess the safety of the therapy in cells and in mouse models of muscular dystrophy. And he’s working with Nationwide Children’s Hospital—home to one of the foremost gene therapy centers in the country—to manufacture and ultimately administer the therapy to Terry, hopefully by August 2020.

This is not biohacking. “This is just fast, rational drug design,” Rich says.

To meet that ambitious timeline, Rich has raised just over $1 million, and he likely needs at least $1 million more. He also needs his collaborators, who have differing opinions on how plausible his timeline is, to work together. And of course, he will need permission from the US Food and Drug Administration to ultimately give the therapy to his brother. “This is a new technology, and super risky,” Rich admits. “The traditional way of drug development is not really working for us,” Rich adds. “So we have to take the big bets here because that’s all we’ve got.”

CRISPR experts contacted about the project were surprised to hear about its anticipated timeline and budget—and that it was happening at all. “It sounds highly optimistic to me,” says Eric Olson, a muscular dystrophy researcher at the University of Texas Southwestern Medical Center. “This is not a trivial undertaking. The manufacturing piece alone is monumental and very expensive. Hopefully they are successful, but it is a tall order.”

Delivering the CRISPR activation therapy into cells will require the use of adeno-associated viruses (AAVs), which are widely used in gene therapies that deliver a therapeutic gene. For Terry’s therapy, the therapeutic gene will be a set of DNA instructions that allows his muscle cells to make the CRISPR activation therapy, which consists of a transcription-activating protein tethered to a modified Cas9 enzyme, and a guide RNA molecule that will direct that complex to a neuronal isoform of exon 1.

Olson has used CRISPR to fix a unique muscular dystrophy mutation in cells donated from a young man named Ben Dupree. But Olson made clear that the purpose of that project was to test CRISPR’s potential for treating muscular dystrophy at large, not to develop a personalized CRISPR therapy for Dupree. “No other person in the world has his mutation. We can correct it, but that’s not our number 1 thing to do,” Olson says. “From a moral perspective, maybe there is a reason to try and develop a therapy that can affect the largest number of patients.”

In 2017, Olson cofounded a start-up called Exonics Therapeutics to develop CRISPR therapies to fix more common muscular dystrophy mutations. He’s also led studies testing CRISPR therapies in dogs, a commonly used animal model of the disease. In June, Vertex Pharmaceuticals announced it would acquire Exonics for $245 million, but it hasn’t disclosed when it will begin testing those experimental therapies in humans. In fact, the first CRISPR therapies for genetic diseases have only just begun the first phase of clinical testing this year. So it is far from a given that the FDA will even allow Terry’s custom CRISPR therapy to be administered.

Because CRISPR activation systems only bind to rather than cut DNA, as the classic CRISPR-Cas9 does, they don’t run the risk of introducing new mutations. “It won’t wreak havoc of cutting the genome everywhere,” Lek says. Charles River will run RNA sequencing on Terry’s cell line and the humanized mouse model to make sure the CRISPR activation therapy doesn’t accidentally boost the expression of genes that could increase the risk of cancer.

Charles River plans on testing Terry’s CRISPR therapy in mice in early 2020. The mice are engineered to have a human dystrophin gene in place of the mouse dystrophin gene. But the team decided that creating a mouse to mimic Terry’s mutation in exon 1 would take too long—potentially delaying the project by an additional year. Lauren Black, the scientist leading personalized drug projects at Charles River, says the current plan is to use the data from Terry’s cell lines to show that the CRISPR therapy works and data from the mice to prove its safety to the FDA.

Rich says they want to avoid something like a dog experiment at all costs. “That would be very time consuming and very expensive,” he says. “We don’t have the wiggle room to go down a rabbit hole that the FDA doesn’t care about, or miss something they do care about.”

Black, a former FDA reviewer and one of the regulatory advisers for Yu’s antisense oligonucleotide drug for Mila, thinks that the FDA will be willing to work with their limited data set because Terry has no other options. “My job as an adviser is to pick the good shortcuts,” she says. “We just want to do what’s necessary. What is it that will be minimally accepted by the regulators? That is our ethic.”

The FDA green-lighted Mila’s drug through an expanded-access investigational new drug application, commonly referred to as “compassionate use.” It’s what experts are calling an n-of-1 treatment—a drug designed and approved for a single individual. While Terry’s mutation is rare, Rich says there are likely other people with exon 1 mutations who could benefit from the same CRISPR activation treatment. For this reason, Rich’s team plans on submitting a traditional investigational new drug application, in which Terry is the first patient, and others could follow behind him.

“We don’t consider this an effort to treat one person,” says Kevin Flanigan, the director for the gene therapy center at Nationwide. Flanigan asserts that Nationwide is not in the business of developing and testing n-of-1 therapies. “The science behind what Rich is proposing to do is compelling and very interesting and may have implications for a much larger set of patients,” he says. “It is imperative that we understand the safety profile of approaches like this.”

“Our reputation is on the line,” Lek says, speaking for the team.

Even as Rich tries to push Terry’s treatment forward, Rich is thinking about how custom CRISPR therapies can be made more quickly for other people in the future. In fact, Cure Rare Disease is already spearheading projects for two boys with different Duchenne muscular dystrophy mutations and a woman with limb-girdle muscular dystrophy. In all cases, the team hopes to use the same AAV and CRISPR activation construct and simply change the guide RNA—the molecule that directs the CRISPR activation machine to a unique location in a person’s DNA—for each individual.


It’s still far too early to know if Rich’s efforts will be successful, let alone repeatable, but he knows that other rare-disease groups will be watching his progress closely. “What we do with Terry, assuming we are the first ones to trial, will really set a significant precedence,” Rich says.