On the Fast Track: Center Collaboration Gives Gene Therapy a Push

Center adviser Fred Gage led the research team.

Last August, newspapers ran the story of an eye-wideningly successful gene therapy study in ALS mouse models. The experiment—by scientists at The Salk Institute in La Jolla, Calif., and at The Packard Center—proved a non-harmful virus capable of carrying genes for insulin-like growth factor (IGF-1) into the animals’ spinal cords.

There, IGF-1, a molecule able to protect cells, worked its effect on motor neurons, slowing the onset of disease. “Not only did the mice live significantly longer,” says Fred Gage, the Center scientific advisor and Salk investigator who lead the research, “but for some time, they were more robust. Their muscles retained normal size, their weight stayed normal.”

And the part most avidly read by patients was that good effects appeared even if the mice didn’t get IGF-1 genes until after disease symptoms had started. “Usually, we test treatments in mice only before they get sick—their illness progresses so rapidly—but this was different,” says Center Director Jeffrey Rothstein, one of the research team.
Now, driven by the need to know if similar therapy would be both safe and helpful in ALS patients, the scientific team is pushing the approach forward. “Because this potential therapy employs genes and viruses rather than a drug,” Rothstein explains, “you have more bases to touch before you can initiate a study in patients. But we’re shaving the time each step requires to its bare bones.”

A virus carries useful genes from mouse leg and diaphragm muscles to key spinal cord motor neurons.

Take the virus, for example. Preparing adeno-associated virus (AAV) for possible clinical trials requires not only a greater quantity of it but also a higher grade of purity than in the animal study. Only a handful of companies has expertise in dealing with AAV and the specialized work comes with a high price tag, says Rothstein, who estimates virus prep and subsequent animal studies will cost around $1.5 million. A search was on before picking Ceregene Inc., a biotech firm in San Diego.

Fortunately, Project ALS has been a great ally and a moving force behind the scientific collaboration. The nonprofit not only funded the lion’s share of the mouse research, but now will help make virus-readying possible.

The final virus has to be safety tested in mice—not a step you can skip. “That typically takes a year,” Rothstein explains, “but the FDA, which approves that phase, may agree to a faster-track approach, given the dire nature of ALS.” Next, the researchers want to test AAV in higher animals to make sure that, as in mice (see diagram), it can carry genes from target muscles into the motor neurons that supply them.

“All in all,” says Rothstein, “we think we’re a year or more away from human trials.”

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