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Positive results of a gene therapy clinical trial for patients with Parkinson's disease

Investigators reported positive interim results of a gene therapy clinical trial for patients with Parkinson's disease.

Neurologix's 12-patient, dose-escalating Phase I trial is the world's first study to use a viral vector ( the non-pathogenic adeno-associated virus, or AAV ) for the treatment of an adult neurological disease.

In the trial, the vector was injected into a specific target site in the brain in order to transfer a gene to treat Parkinson's disease.
The gene encodes glutamic acid decarboxylase ( GAD ), an enzyme which synthesizes the major inhibitory neurotransmitter in the brain, gamma-aminobutyric acid ( GABA ).

The patients with advanced Parkinson's disease received unilateral infusion of AAV-GAD via a hair-thin catheter into the subthalamic nucleus ( STN ), a deep brain structure known to function abnormally in Parkinson's patients.

According to the interim findings, STN AAV-GAD treatment appears to be safe and well-tolerated in advanced Parkinson's disease, with no evidence of adverse effects or immunologic reaction related to the study treatment.

Furthermore, patients in the trial, at one year, exhibited a statistically significant improvement ( 27%, p = .04 ) in motor function on the side of their body correlating to the treated part of the brain, as measured by the Unified Parkinson Disease Rating Scale ( UPDRS ).

In contrast, the untreated side evidenced no significant improvement in the UPDRS score.
Also, activities of daily living, another standard measure of Parkinson's severity which is recorded by the patients themselves, showed a strong trend toward statistical improvement ( p= .06 ).

In addition, fluorodeoxyglucose ( FDG )-PET scans at one year revealed that the treated side of the brain exhibited a statistically significant decrease in abnormal metabolism, while the untreated side showed a further increase in abnormal metabolism.
The imaging results were considered similar to those achieved with STN Deep Brain Stimulation, an treatment which currently represents the preferred surgical approach for advanced Parkinson's disease.

Twelve subjects in total have undergone gene transfer, four in each of three dose cohorts. Seven of the eight patients representing the low and mid-dose cohorts have now been evaluated one year following treatment. Three of the remaining five subjects have been followed for six months and the remaining two for more than four months.

This Phase I trial is the culmination of more than 10 years of basic research. In 1994, Kaplitt was the first author of a paper published in Nature Genetics, along with During as senior author, which demonstrated, for the first time in a preclinical model, that AAV could be a safe and effective vehicle for gene therapy in the brain. Most importantly, AAV has never been associated with any human disease.

According to Kaplitt and During, " The goal of this research is to determine whether we can 're-set' a specific group of cells that have become overactive, causing the characteristic impaired movements associated with Parkinson's disease.
The interim UPDRS scores are highly promising and, if they are borne out with additional data, would be comparable to results seen with STN Deep Brain Stimulation.
Unlike deep brain stimulation, however, our gene therapy approach is much simpler, can be carried out entirely under local anesthesia, and avoids leaving any devices in the body.

The Phase I trial is an open-label dose-escalation study with four patients in each of three escalating dose cohorts. The third cohort of four patients received 10 times the dose of the first cohort.
The 12 patients participating in the trial were diagnosed with severe Parkinson's disease of at least five years' duration and no longer adequately responded to current medical therapies.

Following treatment, patients were evaluated at 1, 3, 6 and 12 months. These evaluations included scoring via the UPDRS, neuropsychological testing, videotaped examinations and timed motor tasks. PET scans were also taken at baseline, 6 and 12 months.

The surgery entailed a stereotactic neurosurgical procedure performed under local anesthesia with the patient awake.
First, MRI was used to image the target subthalamic nucleus ( STN ) region of the brain.
The STN was mapped using microelectrodes by recording from single neurons as the electrode was slowly moved towards the STN.
Once a signature firing pattern was obtained confirming that the electrode was in the STN, the fine-wire electrode was removed, leaving only the microelectrode sheath through which a hair-thin ( 165 micron ) hollow tube was inserted.
Thirty-five microliters containing 3.5, 10 or 35 billion particles ( depending upon dose cohort ) of the AAV ( adeno-associated virus ) viral vector with a human GAD gene ( cDNA ) were then infused at 0.5 microliters/minute, together with 15 microliters of 25% mannitol.
After the 100-minute infusion period, the delivery catheter was withdrawn and the incision closed. No hardware was left behind following this procedure, and all patients were discharged within 48 hours of the procedure.

Source: Neurologix, 2005