Two newly approved drugs slow the progression of the rare and deadly Duchenne muscular dystrophy, but nothing on the market actually reverses the march of the disease. An emerging group of experimental gene therapy and gene editing treatments designed to do so are creeping towards human clinical testing, however, and one of them has just landed in the hands of a new Boston startup, Exonics Therapeutics.
The startup has been seeded with $5 million in funding from CureDuchenne Ventures, a subsidiary of the nonprofit group CureDuchenne. It plans to advance the scientific work of University of Texas Southwestern Medical Center molecular biologist Eric Olson, who has been trying to use the gene editing technology CRISPR-Cas9 to develop a long-lasting treatment for Duchenne.
Patients with Duchenne, who are primarily boys, lose ability to walk by their teens, and often die from complications like respiratory or heart failure at a young age. For years, theses patients had no treatment options. But last September, Sarepta Therapeutics (NASDAQ: SRPT) became the first to win FDA approval of a Duchenne drug, eteplirsen (Exondys 51), and Marathon Pharmaceuticals followed with the second FDA-approved Duchenne-treating drug, deflazacort (Emflaza), earlier this month.
Neither of these treatments are cures, however. Sarepta’s drug is approved for a subset of Duchenne patients, roughly 13 percent with a specific genetic malfunction, for which it is supposed to slow the progression of the disease. Deflazacort is a steroid already widely available in other countries, also meant to help slow Duchenne. Gene therapy and gene editing offer a potentially much longer lasting solution by supplying genetic instructions for a patient’s body to produce a muscle-protecting protein, dystrophin, that people with Duchenne lack.
Gene therapy has been tried for Duchenne before, but never successfully. Yet advances in the delivery vehicles for gene therapy have led to a newer crop of experimental treatments advancing toward human trials. One Boston area company, Solid GT, is advancing into clinical testing a treatment called SGT-001 that came from the research of University of Missouri professor Dongsheng Duan. The therapy is meant to help patients produce micro-dystrophin, a shortened version of the dystrophin protein. And in January Sarepta cut deals for two experimental gene therapy programs from Nationwide Children’s Hospital in Cleveland, one of which is expected to begin human trials late this year.
The newer CRISPR-Cas9 technology—a method of performing genetic surgery—has increasingly been harnessed by academics as another possible method to treat Duchenne as well. In 2015 and 2016, scientific groups at Duke University, Harvard University, UCLA and the Broad Institute of MIT and Harvard, as well as Olson’s team at UT Southwestern, published papers in peer-reviewed journals on preclinical CRISPR-Cas9 work.
Olson’s work, which has become the basis for Exonics, uses an adeno-associated virus—a commonly used delivery tool for gene therapy—to deliver CRISPR-Cas9 into the body. CRISPR-Cas9 is essentially a pair of molecular scissors guided to a cell’s nucleus by a strand of RNA, where it snips out a defective gene—in Exonics’s case, a mutation that prevents the production of dystrophin—and replaces it with a functioning one. The approach, if ultimately successful, could lead to a treatment for up to 80 percent of Duchenne patients.
To be clear, however, there is no human clinical evidence that CRISPR can be used safely and effectively in humans. Trials of the technology are just beginning this year in other diseases like cancer and genetic blindness, and it wouldn’t be surprising to see unexpected problems emerge as these therapies progress forward—it’s taken decades, for instance, for gene therapy to get where it is today, and there are just two gene therapies approved in Europe and none in the U.S. Exonics says it expects additional preclinical data next month, but didn’t say how far it is from human clinical testing.
Jak Knowles, the managing director of CureDuchenne Ventures, is Exonics’s president and interim CEO. Cristina Csimma, former president and CEO of rare disease drug accelerator Cydan, is the executive chairman of Exonics. Olsen is the company’s chief science adviser.