Gene Therapy 3.0: Rise and fall and rise again of gene therapy–For real this time?

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Gene therapy is back in the news, and in a big way as regular readers of the GLP would know. Studies involving the use of gene therapy are showing promising results for the cure of blood disorders, ‘bubble boy’ disease and HIV among others. Industry interest has also picked up and as positive results from clinical trials roll in, the market suddenly appears bullish on the future.

But are we seeing enough to suggest that the technology is promising enough to make a major contribution to public health? Why does gene therapy have to be ‘back’ in the first place?

We offer a quick recap here, but for a more detailed read on the rise and fall (and rise again) of gene therapy, read this excellent narrative by Carl Zimmer in Wired or this comprehensive feature by Laura Cassiday in Nature. Things looked bright for gene therapy in the 90s when it promised to be a revolution that would let us move from just treating genetic diseases to curing them permanently.  The big question surrounding gene therapy had always been how to effectively deliver the correct form of the gene into cells.

Taking a leaf out of nature’s notebook, scientists genetically engineered viruses that could ‘carry’ the correct version of a gene into cells, without producing any of the harmful effects of the virus itself.  Initial results seemed extraordinarily promising, and then things went south really fast.  A patient in one of the clinical trials died as a result of the immune reaction produced by the virus and others in trials in France and the UK developed leukemia as a result of how the virus integrated therapeutic DNA into the genome. These unfortunate incidents struck fear into the collective mindset of the community bringing research and consequently investor interest to a halt.

But since then, researchers have gone back to the drawing board and developed more effective and less harmful viruses to deliver genetic material and treat defective cells or to create cancer fighting cells. Their advances are once again the subject of hot off the press stories that have boosted the confidence of the public and investors alike. But the fall was so hard; it has been a difficult road back for people to become confident again. Regulators in particular have been very reluctant, wary of placing too much trust in a technology that went awry once before. Even as recently as fall 2013, researchers were not quite sure what the future held for gene therapy, as Carl Zimmer reported:

… gene therapy faces an uncertain future. It can be hard to get funding for clinical trials, because the research is so expensive: Even though Wilson’s service can provide a starter kit of the underlying viruses, scaling up production of one vector to serve the needs of a human clinical trial can cost $1 million or more. Pharmaceutical companies, meanwhile, have yet to figure out a business model for gene therapy. Many of these disorders are relatively rare, so the cost of a one-shot cure would need to be cruelly high to recoup initial investment, let alone make a profit.

Its remarkable how much has changed since then. Although the costs and risks involved are still high, nevertheless companies have attracted over $600 million in venture funding in recent years to develop novel cures. Scientists are once again receiving large grants to conduct research that might one day reach the clinic and hopefully into hospitals. Big pharma companies like Pfizer and Novartis that once shied away from the technology are buying in, either creating their own research programs or exchanging their regulatory and manufacturing experience with smaller companies for a piece of the pie. Exciting technologies like CRISPR, the gene editing technique have been added to the mix, making the process much faster offering a lot more potential.

Harry Gruber, an industry veteran and CEO of Tocagen, a gene therapy company spoke about the increased interest in an interview with Nature:

“The investment community has started showing up again at scientific conferences for gene therapy,” [he said]. “The attendance went from basically all scientists to about five investors for every scientist.”

One piece of news is especially encouraging: The Dutch company UniQure, a leading player in the field, had the first drug in the western world approved by the Europian regulatory authorities in November 2012. The drug, called Glybera, targeted patients with a genetic defect that makes them unable to digest fats had shown impressive results in clinical trials. In November 2014, news outlets reported that the drug was finally market-ready, and came with a 1.1 million Euro price tag.

The eye-popping cost aside, this marks a huge step forward for gene therapy as a whole. Though gene therapy treatments for cancer have been available in China for a while now, the data regarding its outcomes has been scant.  But an approval in Europe means the FDA is likely to take a closer look at approving drugs that are showing good results in clinical trials. More importantly, within the next few years, as the results of the use of Glybera in a larger population group come through, regulators will finally have a yardstick to compare other gene therapy drugs to.

The path to the clinic is not easy and appropriately so. The lessons from history are loud and clear – calls for caution need to be heeded to carefully as we continue to push boundaries. And there are other questions to consider as well. For example, how are patients going to pay for this once in a lifetime form of therapy that has never existed in the system before?

But there is enough evidence out there to suggest that the field warrants the big push it is getting right now.  Is all of this enough to say the gene therapy renaissance is for real this time? I think so.

Arvind Suresh is a science communicator and a former laboratory biologist. Follow him @suresh_arvind

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