10/18/05(Neurologix, 2005) - 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.