In gene therapy, the curative gene is packaged in an agent known as a vector, which carries the gene into cells where it is required. One of the most common vectors is derived from a virus, adeno-associated virus (AAV). However, for some diseases, such as recessive Stargardt disease, one barrier to successful gene therapy is that AAV is not able to accommodate the large size of the curative gene. New data, generated by Alberto Auricchio and colleagues, at the Telethon Institute of Genetics and Medicine, Italy, has revealed that vectors derived from a specific form of AAV known as AAV5 can accommodate large genes, including that missing in a mouse model of recessive Stargardt disease.

In the study, it was found that much larger genes could be packaged into vectors derived from AAV5 than from vectors derived from other forms of AAV. Further, it was shown that AAV5 could be used to induce cells to successfully convert the information in the large genes into protein. When AAV5 containing the mouse gene Abca4, which is the mouse correlate of the gene mutated in individuals with recessive Stargardt disease, was injected into the eye of mice lacking Abca4, improvement in the function of the eye was observed. The authors therefore concluded that vectors derived from AAV5 could be useful for treating individuals with recessive Stargardt disease.

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Goydos and his colleagues recruited 11 patients to whom riluzole was administered for two weeks. The researchers tracked the patients' progress before and after the treatment with biopsies and PET scans, a form of nuclear medicine imaging typically used to detect cancer. Our preliminary results show three solid positive responses in nine of the patients who had been able to complete the trial to date, Goydos said. It is actually quite amazing that we got as many as we did.

Goydos also noted that there were other patients in the group who showed some indications of responding to riluzole and they will be reassessed when the trial is completed.

In this situation we hit our target in at least in three, possibly four or five patients, Goydos said. It provides enough data to show that we should go on to a more extensive trial.

The next step is a combined Phase 1/2 trial. Phase 1 will be a toxicity trial where the dosage is increased gradually to determine the appropriate dose and identify possible toxic side-effects.

We will administer riluzole to the first five or six patients, look for toxicity and then move on to Phase 2, Goydos said. We can do this in one combined trial since we are dealing with an FDA-approved drug and not an experimental drug that has never been given to people before.

Goydos said that the Phase 1/2 trial should begin in August, and he anticipates that it will include between 50 and 100 patients with stage 4 melanoma.

I think this drug is going to be extremely important as an adjunct to surgical treatment of stage 3 or stage 4 melanoma, Goydos said. The challenge is to keep it from recurring, which has happened in patients on the order of 50 percent. With low toxicity likely, riluzole could potentially be given for long periods of time to slow down the metabolic processes responsible for the disease's recurrence.

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