LA JOLLA, Calif. – Gene therapy has come a long way from using retroviral vectors to insert gamma-chain transgenes into cells of children with severe combined immunodeficiency in the early 1990s, an act that increased the risk of developing leukemia. (See BioWorld Today, May 1, 2000.)

We've seen the first approval of a gene therapy in Europe. After several attempts, Amsterdam-based Uniqure BV gained European approval for Glybera (alipogene tiparvovec), its adeno-associated viral (AAV) vector for the treatment of the ultra-orphan metabolic disease lipoprotein lipase deficiency. (See BioWorld Today, Nov. 5, 2012.)

In March, Molmed SpA submitted a conditional marketing authorization application in Europe for its genetically engineered cell therapy TK to treat high-risk acute leukemia patients. The Milan, Italy-based company supported the application with a phase I/II study in which 22 of 28 patients who received TK cells achieved immune reconstitution, or recovery of their immune systems. In an ongoing phase III trial, 24 of 24 patients that have completed the entire procedure had a response. (See BioWorld Today, Feb. 5, 2014.)

In June, Bluebird Bio Inc. reported promising results from a phase I/II trial with its gene therapy, Lentiglobin BB305, in patients with beta-thalassemia major. The next-generation vector works much faster than the vector Cambridge, Mass.-based Bluebird initially used seven years ago. The first two patients in the trial became blood fusion-independent on days 10 and 12, respectively, after being transplanted with cells treated with Lentiglobin BB305. (See BioWorld Today, June 17, 2014.)

Panelists from leading gene therapy companies discussed the recent advances in gene therapy during a session at the annual Stem Cell Meeting on the Mesa last week.

"Over the next 12 months there will be substantial de-risking of this field," Douglas Kerr, senior medical director of clinical development at Biogen Idec Inc., told the audience. "In terms of an inflection point for valuation of the field, you're going to get that really soon."


At the heart of the decision about how to treat patients is whether to treat the cells in vivo, inside the patient, or ex vivo by pulling them out of the patient, treating them and then putting the cells back into the patient.

"We've got to get the right tool for the right job," said Faraz Ali, vice president of commercial development at Bluebird.

Because they're treating blood cells, Molmed and Bluebird have both elected to go the ex vivo route, which allows for a controlled environment when the genes are inserted into the cells.

"Some patients are really, really glad that we're not inserting live virus into their body," Ali said.

Of course ex vivo has its disadvantages, too. The procedures require coordination of manufacturing with procedures to remove the cells and transplant them back in to the patient. In vivo techniques using viruses can be manufactured ahead of time and shipped in vials.

AAV has become the in vivo vector of choice because it doesn't integrate into the host DNA, theoretically lowering the likelihood of creating mutations and potentially leading to tumor formation.

Avalanche Biotechnologies Inc. is using an in vivo technique with AVA-101, an AAV vector containing a gene encoding sFLT-1, a naturally occurring anti-VEGF protein, to treat wet age-related macular degeneration (AMD).

As a local treatment through a single subretinal injection, the treatment doesn't need as much virus as a systemic treatment would require. In the Menlo Park, Calif.-based company's phase I trial, AMD patients gained or maintained vision with no need for a rescue therapy at one year after treatment with AVA-101.

Voyager Therapeutics Inc. is also using an AAV vector, but to treat central nervous system disorders. The Cambridge, Mass.-based firm is starting with Parkinson's disease because the affected tissue, mainly the spinal cord and related nerves, is relatively easy to access. (See BioWorld Today, Feb. 12, 2014.)


By avoiding diseases that would require systemic treatment, companies can avoid the problems of having to deliver large amounts of the virus.

Both Avalanche and Voyager also have chosen tissues that offer some protection from the immune system, alleviating the problem of immunogenicity against the vector.

"It's the lower hanging fruit – which is still pretty high fruit," Kerr said of their disease choices.

Immunogenicity for in vivo techniques could become more of a problem if patients need to be retreated. Most gene therapies are designed to be a single treatment, but it isn't known how long the genes will continue to be expressed.

"We're out to six or seven years in the first eye" that was treated, Hans Hull, senior vice president of business operations at Avalanche, said. "In dogs, we're out to 11 years."

There's also the pressing question of intellectual property (IP) with so many companies using AAV to deliver their genes. One solution is to develop AAV variants to avoid IP conflicts and also extend the patent coverage.

"It's a little bit of a to-be-written story," Jeff Goater, vice president of business development at Voyager Therapeutics, told the audience.

And, down the road, there's still the issue of reimbursement to be worked out. As functional cures with a single treatment, gene therapies are quite valuable to the health care system, potentially saving a lifetime of treatment.

But how those payments, which have been spread over decades, will be compressed into a single payment will be a challenge, especially when the duration of efficacy hasn't been established.

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