This past month brought a major milestone for gene therapy, a cutting edge type of medicine meant to permanently alter a patient’s genes to treat disease. For the first time, a gene therapy is available in the U.S., adding to other treatments previously approved in Europe. More are likely on the way, ushering in a new era for genetic medicine.
Yet despite all the progress made with gene therapy, it remains imperfect and relegated to a small group of rare diseases. Increasingly, startups are emerging with creative solutions to address these problems and expand the reach of genetic medicine. Two of them, Generation Bio and Stoke Therapeutics, are debuting this morning.
First up is Generation, a Cambridge, MA, startup with a $25 million Series A round from Atlas Venture and former Swedish Orphan Biovitrum CEO Geoffrey McDonough at the helm. Generation is attempting an unusual gene therapy approach meant to make the technique available to more people, and possibly allow them to get a second dose if the first wears off.
Second is Stoke Therapeutics, another startup that as Xconomy reported in November is run by former Sarepta Therapeutics (NASDAQ: SRPT) CEO Ed Kaye. Stoke is trying to address a current weakness of gene therapy—the inability of developers to control the level of the therapeutic effect. The hope is that Stoke’s treatments will treat diseases that current gene therapies can’t touch. It has raised $40 million from Apple Tree Partners.
These startups emerge at a time in which gene therapies have, at long last, made their way to the U.S. markets. In 2017, the FDA approved three treatments that modify a patient’s genes to treat disease—two for blood cancers, and one for a rare form of inherited blindness. Others are making clinical progress in blood diseases like hemophilia and beta-thalassemia, rare disorders such as Duchenne muscular dystrophy, and more. Two gene therapies were approved earlier in Europe, from UniQure (NASDAQ: QURE) and GlaxoSmithKline (NYSE: GSK).
These developments are the culmination of decades of scientific research on how to effectively and safely deliver genes to cells. Gene therapies shuttle DNA material into the body, typically with the help of an engineered virus, to help the body produce a critical protein—in perpetuity, theoretically. In hemophilia patients, for instance, experimental gene therapies help people make proteins that clot blood. Spark Therapeutics’s (NASDAQ: ONCE) recently approved voretigene neparvovec (Luxturna) helps patients produce a protein that makes light receptors work in the eye.
Ideally, these therapies would require only a single, curative dose. But the problem is gene therapy remains somewhat unpredictable. Developers still don’t know how much of a protein a gene therapy might produce for each patient. BioMarin Pharmaceutical’s (NASDAQ: BMRN) hemophilia A gene therapy has produced, in some cases, stunning results, but the treatment’s therapeutic effects have varied widely from patient to patient. The therapies are costly to manufacture mainly because of the need to engineer and make the gene-delivering viruses.
Durability of the treatment’s effect is also an open question. Another one is whether people will develop resistance to the gene therapy that would render a repeat dose ineffective, because of pre-existing antibodies that can attack the viruses and shut down the treatment.
“Because of the immune responses, you have one shot at it and that’s your lot,” says Pieter Cullis, the director of the Life Sciences Institute at the University of British Columbia, who has been developing delivery technologies for gene therapies and other medicines and isn’t involved with Generation or Stoke.
New startups anticipate that these problems may stymie the reach and potential of gene therapy, and are developing workarounds to broaden its use. Stoke CEO Kaye calls the movement “gene therapy 2.0.” Companies such as MeiraGTx and Intrexon, for example, have been developing “genetic switches” to try to dial up or down the effects of gene therapy. Selecta Biosciences (NASDAQ: SELB) has a technology meant to suppress the immune reactions that can stifle gene therapies.
Generation Bio and Stoke are now in the mix as well. Generation is based on a discovery of former NIH scientist and UMass Medical School adjunct professor Robert Kotin. He published a paper in 2013 outlining the use of a type of genetic material—closed ended DNA, or ceDNA—for gene therapy. This eukaryotic DNA is packaged inside a lipid nanoparticle—essentially a fat bubble, a commonly used drug delivery tool—that is then injected into the body. The LNP dissolves once in the cytoplasm of a cell, and the ceDNA, on its own, heads to the nucleus to produce proteins.
The key, and potentially important difference between Generation’s approach and conventional gene therapy is it doesn’t involve the use of a virus. As CEO McDonough explains, that could provide three key advantages. The first is patients shouldn’t develop antibodies against the treatment. And because of this lack of immunity against the treatment, Generation can start with a low dose and administer it again if needed. Lastly, without the virus, the treatment could be cheaper to produce and easier to scale. “We’re just at the very narrowest beginning of what gene therapy and genetic medicine can do,” McDonough says. “I think this is really a pretty extraordinary jump forward based on where we are today.”
Cullis notes that Generation will still have to watch out for any unexpected safety problems from the use of its ceDNA, but added that its efforts are an example of the “growing awareness” in biopharma of tools other than viruses to broaden the use of genetic medicine. Intellia Therapeutics (NASDAQ: NTLA), one of the developers of CRISPR-Cas9 gene editing drugs, for instance, plans to use LNP technology to deliver a variety of its treatments. “I think you’ll find a fair number of them in the backroom are working on the non-viral approaches,” Cullis says.
Stoke, meanwhile, isn’t using gene therapy per se, but its approach is meant to do what gene therapies can’t: fine tune the level of protein made by treated cells. Stoke, formed by Adrian Krainer, the inventor of the RNA spinal muscular atrophy drug nusinersen (Spinraza), has found a way to efficiently identify segments of genes that can be targeted with a drug to dial up how much of a protein the body produces. Stoke then develops RNA drugs that target these key parts of the genome.
This precise control might be useful in, for example, autosomal dominant diseases, where mutations in just one copy of a gene reduces the amount of a particular protein. In these situations—genetic causes of epilepsy, for instance, Kaye explains—patients might need to get to normal levels of the protein, but overshooting it could be disastrous.
Both Generation and Stoke have much to prove about their respective approaches—they each expect to be in human trials in about two years. But that will still leave plenty of time for each to make their mark if gene therapy’s problems persist.