produce the viral vectors for its gene therapy and conduct some of the preclinical work like toxicity studies, Salzman says.
Aubourg, Puccio, and Crystal are all scientific founders of AAVLife, along with Pierre Bougneres, a colleague of Aubourg’s. The group put together a preclinical study that was highlighted in Nature a few weeks ago, in which a team of researchers administered a gene therapy to genetically-modified mice that reversed the weakening of the heart muscle that’s typically associated with Friedreich’s.
Specifically, the researchers engineered mice with a deleted FXN gene, to simulate Friedreich’s Ataxia, and then delivered an adeno-associated virus, or AAV vector carrying a healthy version of it via an injection directly to the heart. Salzman says that the cardiomyopathy in these genetically-altered mice—the deterioration of the heart muscle—was reversed. Biomarkers judging muscle strength like “ejection fraction,” the heart’s ability to pump out blood, improved and within a week they ended up healthy like any other normal mouse.
“That’s the first time any kind of result like that was seen,” she says.
Of course, curing these symptoms in mice is one thing. Translating that to a gene therapy for people—and effectively delivering it—is a whole different challenge. A particular problem is the fact that AAVLife will have to deliver this therapy directly to the heart without doing more harm than good—and cause heart cells to express enough frataxin. Salzman says the company is now experimenting in pig studies to find out if it would be more effective to inject viral vector carrying the FXN gene directly into the heart muscle, or deliver it less invasively, between coronary arteries. That delivery challenge would get more significant if AAVLife tries to cure the neurological symptoms of Friedreich’s as well. The company is considering options like injecting a second gene therapy into the spine, whether to do two procedures simultaneously, or one after the other.
“We’re looking at what the smartest way of doing it is,” Salzman says.
Part of the reason Salzman is optimistic AAVLife can conquer the delivery issue is the vector choice. AAVLife is using a vector licensed from Washington, DC-based ReGenX Biosciences, a company that other recent gene therapy startups Dimension Therapeutics, Audentes Therapeutics (another Versant-backed company), and Paris-based Gensight Biologics have tapped for assistance with their therapies. The vector AAV life has chosen has already been used in human studies Crystal has performed, and tends to target cardiomyocytes, the heart’s muscle cells, according to Salzman. In theory, this would mean that there’s less of a risk that the virus would wander off and infect other tissue.
The biology behind Friedreich’s is well understood, and a number of companies are working on cures, but so far there are no approved treatments. Versant’s Woiwode says this is partly because most approaches have tried to essentially mop up the damaging byproducts that cells in Friedreich’s patients end up producing, rather than attacking the source of the disease.
There’s a long road ahead to show AAVLife’s approach will work where others haven’t. AAVLife is using the Series A cash to do all of its preclinical work and kick off a clinical trial at some point next year. But assuming things go well and AAVLife establishes proof-of-concept for its gene therapy, that could open some strategic doors. After all, that’s how a 17-year-old, struggling biotech called Genetix Pharmaceuticals ended up with a $35 million round from Third Rock and Genzyme and turned into Bluebird.
“Obviously we won’t know until we go into humans, but in the scheme of things, to have a good mouse model, to have the kind of results that it had, to have a patient association with a registry of over 1,300 patients with their act together, with all the other elements, we had to do something for patients knowing how good the backdrop was,” Salzman says.
