Gene therapy's coming of age

Why gene therapy is hot after more than 20 years of research

After more than 20 years of trial and error in gene therapy, the field is taking off with one product approved in Europe, several poised to enter the market in the U.S., a surge of newcos, and investments of almost $6 billion in the last 18 months. While most experts polled by BioCentury agree that advances in vector technology have laid the groundwork for the recent ramp-up in activity, some say the real catalyst has been the explosion of interest in orthogonal technologies such as CAR T cells and gene editing.

"This is truly a moment in time for gene therapy. It has been a long journey in industry and academia to get to this point," said Annalisa Jenkins, CEO of Dimension Therapeutics Inc.

Since the 1980s, academic researchers have been exploring the idea that adding correct versions of dysfunctional genes to a patient's genome could treat or even cure genetic diseases. The idea seemed simple: engineer inert viruses to insert a therapeutic gene into a cell's nucleus or nuclear DNA, and replace the deficit without causing any pathology.

But the platform wasn't as simple as researchers anticipated, and early clinical trials met with serious problems ranging from limited efficacy to severe immune reactions. Patient deaths in separate gene therapy trials in 1999 and again in 2003 set the field back and led most gene therapy companies to exit the space in the early 2000s.

The consensus was that the vectors - while thought to be harmless - in fact caused the early setbacks.

"People failed to anticipate the immunological consequences of the viral vectors," said Sam Wadsworth, CSO of Dimension.

While the vectors didn't cause viral disease in patients, they were recognized as foreign by the human immune system, he said. That caused two principal problems: First, the vectors were destroyed by the immune response before they could deliver their therapeutic payloads; and second, they stimulated dangerous inflammatory side effects.

There were other complications as well. While early gene therapies focused on indications such as cystic fibrosis (CF), which was thought to be a good candidate as a simple, monogenic disorder, researchers underestimated the complications caused by the disease biology, Wadsworth said. "In CF, the cells you need to target are covered in mucus and inaccessible."

Jeffrey Marrazzo,

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