As R&D setbacks multiply, a pioneering CRISPR/Cas9 program for Duchenne MD continues to impress in new dog study

While one drug after the next seems to get regularly shot down in Duchenne muscular dystrophy, as we saw today with Pfizer’s failed Phase II, a preclinical CRISPR gene editing program has been making some impressive progress in animal studies.

Thursday afternoon, Exonics provided some intriguing details to show how their gene-editing approach works in dogs. Dispatching a Cas9 scalpel with guide RNA inside an AAV delivery vehicle straight to muscle cells, the researchers say that their approach was able to restore dystrophin production that reached up to 92% of normal in a canine model for the disease.

That was for the highest dose used.

John Ripple

“Typically,” Exonics CEO John Ripple tells me, the response in dystrophin production “was above 50%.”

That’s a big deal, he says, particularly when researchers in the field see patients turn asymptomatic at around 20% of normal dystrophin production.

Exonics has been making measured advances in this field, starting with the lab work done by UT Southwestern’s Eric Olson, who did the early scientific investigation using CRISPR on cells and mice. We made contact early on, as he discussed the progress he had been making. Olson co-authored the study out today.

“Canines have clinical and pathological features similar to the human presentation of Duchenne, including muscle weakness, atrophy and fibrosis,” Olson noted today, as the latest work appeared in Science.

Late last year a $40 million launch round helped the company get started with a virtual crew, which is now growing fast. From a handful of staffers, Exonics roster has now grown to 11, with plans to double that when they move into a new lab and offices in Watertown later this year. 

In many ways, Duchenne MD could prove one of the best fields for a CRISPR team to work in — especially in the early days.

In this case, they’re looking for a simple cut and repair response needed to correct errant cells that trigger the ailment, which slowly but surely cripples and then kills its victims. Targeting muscles and heart tissue gives them a stable group of non-dividing cells to work with, which may well reduce the chances of any off-target impact — a topic that routinely sparks near panic in CRISPR/Cas9 investment circles.

It should be noted, though, that before we start spotlighting a potential cure for Duchenne, or specific genetic patient populations with the disease, the drug is still not ready for a prime time human trial.

“Our next step is to continue preclinical work, advancing in the clinic,” adds the CEO. “We need to do longer animal studies, maintain dystrophin protein over a long period of time.”

That way, by the time they sit down with regulators and start talking human studies, they’ll be able to make a solid case built on extensive preclinical work. Whenever that day arrives.

There’s not an unlimited amount of time available, though. Patients are still in desperate need, and other biotechs are also working on a cure.

Exonics is one of several developers looking to carve a new research path to this disease. Muscle drugs have proven very problematic in addressing a severe disease like this. And Sarepta’s eteplirsen was approved without significant efficacy data, underscoring a dramatic need for new drugs. Sarepta, Solid Bio and others are exploring gene therapy approaches, which have also highlighted some impressive early results.

Image: Eric Olson. Jane Coffin Childs Memorial Fund for Medical Research

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