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Bluebird’s Gene Therapy Quickly Halts Blood Disease in Small Study

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be durable, and see similar success with other beta-thalassemia patients. At this point, two other patients have been enrolled in the HGB-205 trial, and neither has been treated yet, according to Leschly. Once the trial is complete, Bluebird can begin to think about taking Lenti-Globin into a further trial, and discussing with the FDA what would be required to get the treatment approved. (The FDA has never approved a gene therapy. The only one that’s approved by regulators is sold by UniQure in Europe.)

The central challenge of gene therapy has always been inserting corrective genes into enough cells to make a difference in the disease being treated. It’s also crucial that those cells survive and divide, thus creating a self-perpetuating population of cells that make working versions of the protein that’s defective in the disease.

For years, scientists experimented with using modified adenoviruses, similar to cold viruses, to insert genes. But the efficiency of gene transfer was often low—and the adenoviral vectors could trigger immune reactions. In 1999, a severe immune reaction from an adenoviral vector killed a gene therapy patient, slowing progress in the whole field. Now, many gene therapy hopefuls use tiny adeno-associated viruses (AAVs), which are thought to be safer than adenoviruses, as their vectors of choice.

Bluebird has taken a different tack, turning to lentiviruses as the gene therapy vector. Like HIV, these viruses are able to deliver large amounts of genetic material into cells—and have the added benefit (for gene therapy) of being able to infect non-dividing cells. Lentiviruses are particularly useful for Bluebird, though, because it wants to deliver genes to the stem cells found in a patient’s bone marrow and perpetuate the genetic change when those cells divide.

The two-patient cohort seems tiny, but it was a similar small sample size that effectively saved the company. Founded as Genetix Pharmaceuticals almost 20 years ago, it was surviving on bridge loans when a study published in 2009 in Science showed that its approach to gene therapy was able to slow the progression of childhood cerebral adrenoleukodystrophy (CCALD), a crippling genetic disorder affecting the brain, in two children. Third Rock Ventures and Genzyme stepped in with existing backers like Easton Capital and TVM Capital and put $35 million into the company. Leschly, a former project leader for bortezomib (Velcade) at Millennium Pharmaceuticals, was at that point a Third Rock partner, and took over as interim president. He eventually left the firm to head Genetix, which was renamed Bluebird in September 2010.

Then, Bluebird was able to show that its older-generation lentiviral vector, HPV569, helped a single patient in France become transfusion-free after a year (a second patient who got the treatment didn’t have the same response). That, along with the CCALD results, helped fuel Bluebird’s big IPO last year.

So why is the new vector better? Without divulging specifics, Leschly calls the changes “hard core improvements in the manufacturing.” The company focused on making a purer virus that could infect more cells, meaning Bluebird could use less of it, but get the same type of results, he says.

The approach seems to be solving that central problem of gene therapy: lack of efficacy. The improved Lenti-Globin vector appears to insert the corrective gene into enough cells to make a clinical difference—at least so far, since the two new patients haven’t yet needed blood transfusions and their hemoglobin levels have remained high.

That implies that the genetically modified cells must be dividing and reproducing, repopulating the bone marrow. If the cells weren’t reproducing, hemoglobin levels would drop as the original modified cells died off over a period of weeks (as happens with cells added through a transfusion). “We’re not seeing that, certainly in the first patient,” Leschly says.

Leschly also notes that the beta-thalassemia patient who got HPV569 several years ago and responded is still producing enough hemoglobin to stay clear of transfusions, even with an earlier, presumably less potent vector.

“Obviously time will have to tell, but that’s what’s giving us a lot of promise even though the numbers are small,“ he says.

Ideally, that increased potency from the new vector is a sign of things to come in other trials with Lenti-Globin. Leschly says, for example, that the manufactured genes in Lenti-Globin have an “anti-sickling” property that could help with sickle-cell disease—along with beta-thalassemia, the two most common genetic disorders in the world—while boosting hemoglobin. Bluebird has a trial open to find out.

Other answers are on the way, as well. Bluebird has a second, larger beta-thalassemia study in the U.S. called “Northstar” that it’s hoping to share some data from in November. Six of an anticipated 15 patients have been enrolled in that study so far, according to Leschly, and one has been treated. Updated results from the HGB-205 trial are on the way as well. A Phase 2/3 trial called “Starbeam” testing its other vector, Lenti-D, for CCALD, will wrap up further down the road—Bluebird aims to complete enrollment in 2015.

“As we get more data, we’ll have the appropriate dialogue with the thought leaders and the regulatory agencies to determine what the appropriate next steps are,” Leschly says. “We don’t know those answers yet. First things first, continue to follow and treat more patients, that’s really our focus.”

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  • peacemaker

    My daughter has beta thalassemia major. She’s only three years old and she’s being treated at Children’s Hospital in Oakland, Ca. I must admit after reading this article I shed tears of joy, hope, and fear. First I would like to congratulate those brave souls who have volunteered to try out this new gene-therapy, I pray them success. To be honest I became very fearful when I realized that a virus was being used to manipulate the stem-cell. All I can do now is hope that these awesome volunteers are different enough that the specialist’s can factor out any unpredictable variables that may cause some problems, and (GOD forbid) if there were any problems could the process be reversed, i.e. removing those modified stem cells? Just random emotional thoughts.