Gene therapy has finally made it over the hump.

After decades of research and some devastating setbacks, major technical hurdles have been overcome, opening up the long-anticipated promise of this field. A new approval has buoyed interest, pipelines are bubbling with new candidates and big investments are being made.

Two gene therapies have hit the European market and the first is expected to hit the U.S. market as early as next year. Beyond that, there is a growing pipeline rapidly coming forward.

All this is fueling high hopes of actual cures for previously incurable diseases and big profits. So whats the rub?

The first ever approved gene therapy was Shenzhen SiBiono GenTechs Gendicine, a recombinant Ad-p53 gene therapy for head and neck cancer, which launched in China in 2004. But it was Glybera's (alipogene tiparvovec) approval in fall 2012 that sparked investor interest in gene therapy. For a while that drug reigned as the most expensive treatment in history, costing more than $1 million per patient.

Glybera turned out to be a disappointment due to the high price tag. The drug restores lipoprotein lipase enzyme activity in patients with LPL deficiency (an ultra rare disease), but the drug comes with the severe side effect of pancreatitis. After use by only one patient and five years on the European market, maker uniQure chose not to seek renewal of its European approval this fall and is not pursuing U.S. approval.

Despite the failure of Glybera, GlaxoSmithKlines Strimvelis has further fueled investor interest with its approval in Europe in May 2016.

Strimvelis treats severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency. It is estimated that about a couple dozen children per year are diagnosed with ADA-SCID in the U.S. and Europe combined. One year on the market, the British pharma has confirmed that one patient has been treated with the drug. "A patient has been treated with Strimvelis and others have been referred and are currently being assessed for eligibility to receive the drug," GSK spokesperson Anna Padula told BioPharma Dive.

After the Glybera debacle, GSKs experience with Strimvelis will be telling, but there are also some up-and-coming gene therapies that may teach us more.

Gene therapy was originally regarded as one of those "no-brainer"approaches to curing genetically caused diseases. After all, if the DNA is broken, why not just fix it? Unfortunately, it turned out to be much more complicated.

Many of the challenges are around how new DNA is incorporated. One choice is to inject a viral vector attached to a payload that naturally integrates its genetic material into that of the patients. The other choice is to remove the patients cells, modify them, and return them, a process known as ex vivo therapy.

One of the early fears was that DNA would incorporate in the wrong place thereby not fixing the error, as well as creating a new one. That turned out to be a real worry with some of the first vectors, reinforced by early gene therapy treatments for SCIDS that led to T-cell leukemia in some treated boys. At least one of those boys died from the cancer they developed.

Further, there was the tragedy of Jesse Gelsingers death at the University of Pennsylvanias Institute of Human Gene Therapy in 1999. Eighteen-year-old Gelsinger was taking part in a trial aimed at treating ornithine transcarbamylase deficiency, but just days after receiving the therapy he died of massive organ failure, likely sparked by an immune reaction to the adeno-viral vector used.

Then there were treatments that just didnt work. Avigens gene therapy worked well in animals, producing adequate Factor IX levels for several years in models of hemophilia. But in clinical trials, only one patient responded, and that response lasted only four weeks. The patient, as one observer noted, had "touched the rainbow" only to watch it fade from view.

Beyond efficacy, manufacturing is still a challenge. "But we are getting better at that and in the selection of indications," said Scott Burger, principal at Advanced Cell and Gene Therapy. Because gene therapy is such a young field, Burger noted that "long-term monitoring of patients will be key." The boys who developed leukemia in the early SCID trial were all diagnosed a couple of years after treatment.

Every field has its ups and downs, but these tragic events left gene therapy with tremendous baggage. Still, some dogged proponents have soldiered on, and the news now more than a decade later seems to be getting a lot better.

"A new generation of vectors have dramatically improved the prospects for this field," said Geoff MacKay, President and CEO of AvroBio. "There are now hundreds of gene therapies that are in trials and many of them are a one time cure."

News about promising gene therapies in the clinic is sprouting up all the time.

BioMarin has a gene therapy for hemophilia A in Phase 2b. "We are far ahead in the development process and could potentially market the first gene therapy for this condition," said company spokesperson Debra Charlesworth. "The physician and patient community will be looking for strong clinical data," she added. "In addition we have commissioned a gene therapy manufacturing facility that will come online in the middle of this year."

GSK has a license to develop multiple new gene therapies with Fondazione Telethon and Ospedale San Raffaele, the same groups that helped produce Strimvelis. The agreement covers six additional treatments, including one for metachromatic leukodystrophy and one for Wiskott-Aldrich Syndrome. Padula reports that both of these are in clinical trials.

The next wave of gene therapies will focus on rare diseases like hemophilia and even inherited forms of blindness.Spark Therapeutics, for example,recently submitted a Biologics License Application (BLA) with the FDA for voretigene neparvovec, a gene therapy for the treatment of vision loss due to biallelic RPE65 mutation-associated retinal disease.

And Pfizer has inked deals with both Spark and Sangamo for gene therapies to treat different forms of hemophilia. Meanwhile, Biogen spin-off Bioverativhas picked up two gene therapies from Sangamo.

Scientific challenges remain considerable, though, and pricing will clearly be one of the biggest hurdles for gene therapies going forward. "Todays challenges are all around building a viable business model," said MacKay. That has not dampened enthusiasm for the blossoming field that has been rising and falling out of favor for at least two decades.

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A new wave of gene therapies ready to hit US shores - BioPharma Dive