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AAVLife Gets $12M to Bring Gene Therapy to Rare Ataxia

Xconomy Boston — 

Bluebird Bio is a symbol, in a way, of the renaissance of gene therapy. The Cambridge, MA-based company raised $116 million in an IPO last year, and a number of startups pursuing gene therapy have cropped up since. So perhaps its no surprise that the field’s new entrant, AAVLife, comes from some of the same people that indirectly helped Bluebird get off the ground a few years ago.

Today, AAVLife is emerging from stealth with the help of a $12 million Series A round led by San Francisco-based Versant Ventures and the Inserm Transfert Initiative, a venture arm of the French Institute of Health and Medical Research. The funds will help Paris and New York-based AAVLife build on an animal study just published in Nature in which researchers used gene therapy to curb the cardiological dysfunction associated with Friedreich’s Ataxia, a rare, often fatal, genetic neuromuscular disorder that causes a progressive loss of motor function, among other things. AAVLife has been built to advance that work into clinical trials and hopes to get its first human study up and running in early- to mid-2015, according to CEO Amber Salzman.

To be clear, at this point, AAVLife isn’t trying to cure Friedreich’s outright—just the part of it that affects the heart. But Salzman says the biggest reason people with Friedreich’s end up dying young is heart failure from the damage that accompanies the neurological symptoms. So on one hand, reversing these effects would still leave Friedreich’s sufferers dealing with the neurological symptoms of their disease, which get progressively worse and can often leave patients in a wheelchair. On the other, these patients would theoretically get many more years, “possibly decades” of life, says Versant venture partner Thomas Woiwode.

“The thought from the patient groups and everyone involved has been, if we can make sure that [these patients] live and they don’t die of heart failure in their 20s, that’s a huge benefit. We didn’t want to slow down anything just because we couldn’t cure everything,” Salzman says. “But we are very rapidly looking at what’s the best way to approach getting to the other cells as well.”

AAVLife’s roots can be traced back to Bluebird (NASDAQ: BLUE). About 12 years ago, Salzman’s nephew and later her one-year-old son were diagnosed with x-linked adrenoleukodystrophy, a crippling genetic brain disorder. Salzman, then an R&D executive at GlaxoSmithKline, took action: she dove into research, helped form the Stop ALD Foundation, and began collaborating with pediatric neurology specialist Patrick Aubourg. The two began thinking about a gene therapy approach to treat the disorder, which is triggered by a specific genetic mutation.

AAVLife CEO Amber Salzman

AAVLife CEO Amber Salzman

Through her foundation, Salzman helped coordinate the backing to advance the concept, ultimately leading to a successful gene therapy procedure that Aubourg helped perform on two boys with ALD. The results of that study were published in Science, and Third Rock Ventures and Genzyme took that work forward in the form of Bluebird, now a publicly-traded company with a roughly $500 million market cap.

“When it comes to rare diseases, when you get a passionate and effective foundation behind it, it’s amazing what they can pull off,” she says.

Salzman and Aubourg kept working together over the next few years, even as Salzman took over a startup called Cardiokine and eventually sold it to Cornerstone Therapeutics in 2011. Aubourg was looking into treatments for other rare, neurodegenerative diseases—among them Friedreich’s. The disease is caused by a mutation to the FXN gene, which leads to low production of frataxin, a protein that helps mitochondria—the cell’s power plants—function normally.

Aubourg convinced Salzman to take a project on and form a company with him once she sold Cardiokine. With some pressing from the Friedreich’s Ataxia Research Alliance, Salzman decided to center the project around a therapy for Friedreich’s. She then helped bring together an international team of researchers and gene therapy experts to work on the project—among them Ronald Crystal of New York’s Weill Cornell Medical College and Helene Puccio of the University of Strasbourg in France. With the group in place, AAVLife officially formed in January.

Indeed, while AAVLife is a small startup at this point, it’s also an international effort. The company’s offices are in Paris, where it can tap into Inserm for R&D help, but it’s also leaning on Crystal in New York to 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.

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One response to “AAVLife Gets $12M to Bring Gene Therapy to Rare Ataxia”

  1. Melissa Gordon says:

    Thank you for never giving up on our kids. I can’t begin to tell you how happy this makes FA families. We are giving our kids their future back.

    Melissa Gordon