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Diamyd Medical AB believes its vaccine method for saving insulin-making beta cells in Type I diabetics using glutamic acid decarboxylase 65 (GAD65) might stop or slow the march of the disease in recent-onset patients.

Stockholm, Sweden-based Diamyd, which has filed an investigational new drug application for a Phase III trial, plans to file similar paperwork for a parallel European study, and hopes that two 300-patient trials with favorable data could lead to approvals. Meanwhile and separately, GAD65 is gaining ground elsewhere, too - in gene therapy, at Neurologix Inc.

Saving beta cell function, thus keeping the endogenous-insulin machine cranked up, is the best way of reducing late-stage complications for diabetics, and the planned Phase III trials will test Diamyd in patients diagnosed as long as three months earlier.

As determined earlier with the FDA, the primary endpoint will be a measure of meal-stimulated C-peptide, as a correlate for the patient's own ability to make insulin. Other endpoints - the patients' insulin requirement and glycemic factors - will be watched, as well, and results will be evaluated after 15 months.

GAD65, a major autoantigen in autoimmune diabetes, also functions as an enzyme that converts the excitatory neurotransmitter glutamate to GABA, so the drug also might work in central nervous system-related diseases.

Diamyd Medical owns an exclusive worldwide license from the University of California at Los Angeles regarding the therapeutic use of the GAD65 gene, and Neurologix, of Ft. Lee, N.J., holds a sublicense for a Parkinson's disease gene therapy using an AAV vector.

Earlier this month, the FDA granted fast-track designation for Neurologix's gene-transfer procedure, which delivers GAD65 to the subthalamic nucleus of the brain, and the company is preparing to start a Phase II study in early 2008. The subthalamic nucleus is the same region targeted by deep brain stimulation, one of the few treatment options for patients with advanced Parkinson's.

Officials at Diamyd could not be reached, but John Mordock, president and CEO of Neurologix, said his firm has high hopes for the GAD65 approach as well.

GABA, he noted, is "well distributed throughout the entire brain," acting as a neuromodulator in several areas, including the basal ganglia.

"Dopamine really begins to express the GABA, but [in Parkinson's disease] the neurons that would normally express GABA have reached the point where they've either died off or become inefficient," Mordock said, but GABA is the key.

"Essentially, in the absence of GABA, there's nothing to offset the high levels of acetylcholine" characteristic of Parkinson's, he said, adding that Neurologix's is the only nondopamine-centered gene therapy, called NLX-P101, in the works. Advantages could include avoidance of such adverse effects as dyskinesia (tics or spasms), since dopamine, while compatible with the basal ganglia, causes trouble in other parts of the brain.

"If you take a look at what's going on in small molecules, the current thinking is to try to develop GABA producers," Mordock told BioWorld Today. "But if you give someone a pill, you can get a large enough dose to get an effect on the other side of the blood-brain barrier. We're going directly in."

Neurologix's approach uses a catheter delivery system. The safety profile so far is "pristine," Mordock said, and the method lacks the risks associated with other gene therapies.

"We're working on the other side of the blood brain-barrier, and we're not trying to kill anything," he said.

The Lancet this summer published results from Neurologix's first trial, an open-label Phase I study in 12 patients with advanced Parkinson's. Researchers found no adverse and statistically significant improvements from baseline in both clinical symptoms and abnormal brain metabolism, as shown in PET scans. The procedure was performed on only one side of the brain, which let the untreated side serve as a control. Improvements started three months after the procedure, and persisted through the 12-month study period.

In November, the Proceedings of the National Academy of Sciences online published more results indicating the approach's ability to quiet abnormal brain activity that goes along with motor deficits in Parkinson's.

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