Contact: Jonathan Weil
[log in to unmask]
212-821-0566
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell
Medical College

Promising results from first gene therapy clinical trial for Parkinson's
disease reported
Patients' motor skills improved with no major side effects, Weill Cornell
team reports
NEW YORK (June 21, 2007) -- In what could be a breakthrough in the treatment
of neurological disease, a team led by physician-scientists at
NewYork-Presbyterian Hospital/Weill Cornell Medical Center has completed the
first-ever phase 1 clinical trial using gene therapy to battle Parkinson's
disease.
The study of 11 men and one woman with the progressive neurodegenerative
illness found that the procedure -- in which surgeons inject a harmless
gene-bearing virus into the brain -- was both safe and resulted in improved
motor function for Parkinson's patients over the course of one year. The
findings are published in the June 23 issue of The Lancet.
"These exciting results need to be validated in a larger trial, but we
believe this is a milestone -- not only for the treatment of Parkinson's
disease, but for the use of gene-based therapies against neurological
conditions generally," says lead researcher Dr. Michael Kaplitt, associate
professor of neurological surgery and the Victor and Tara Menezes Clinical
Scholar in Neurological Surgery at Weill Cornell Medical College, and
director of Movement Disorders Surgery at NewYork-Presbyterian
Hospital/Weill Cornell Medical Center.
Dr. Kaplitt has devoted much of his academic research career to the
development of effective gene therapy techniques against Parkinson's disease
and other neurological disorders. In fact, 13 years ago, he and Dr. Matthew
During pioneered a now widely used gene-delivery technique for the brain
using an altered, harmless form of adeno-associated virus (AAV). In 2003,
Dr. Kaplitt performed the world's first gene therapy surgery for
Parkinson's, conducted at NewYork Presbyterian/Weill Cornell.
"Viruses exist in nature mainly to transfer their own genes to the host
cell," he explains. "So, we modify the AAV in such a way that the only gene
it carries is the one we want to deliver to the therapeutic site."
In this case, the "gene of interest" is the glutamic acid decarboxylase
(GAD) gene. "GAD makes a chemical called GABA, a major inhibitory
neurotransmitter in the brain that helps 'quiet' excessive neuronal firing,"
explains Dr. During, the senior author of the current study, who worked on
this research while at Weill Cornell. Dr. During is now professor of
molecular biology and cancer genetics at Ohio State University.
"In Parkinson's disease, not only do patients lose many dopamine-producing
brain cells, but they also develop substantial reductions in the activity
and amount of GABA in their brains. This causes a dysfunction in brain
circuitry responsible for coordinating movement," Dr. During explains.
The researchers' bold idea: to insert the GABA-producing gene GAD back into
an area of the brain called the subthalamic nucleus, a key regulatory center
within this motor circuit.
"Our hope was that with a single operation to this single site, we could
boost GABA production and thereby normalize the function of the entire
circuit," Dr. Kaplitt says. "Not only would this alter the chemical balance
in the subthalamic nucleus; it should also provide GABA to other parts of
the network that weren't getting enough of the neurotransmitter."
To test that theory, the investigators injected the GAD-bearing AAV vector
into the subthalamic nucleus of each of the 12 Parkinson's patients, but
only on one side of their brains.
"Because this was the first such study of its kind, we targeted just one
side of the brain initially out of concerns for the patients' safety," Dr.
During says. "However, since the patients were symptomatic on both sides of
the brain, this also provided an untreated side for comparison with the
treated hemisphere."
The researchers then used a standard assessment of motor function, the
Unified Parkinson's Disease Rating Scale (UPDRS) to track changes in
patients' symptoms over the next 12 months. They also tracked changes in
each patient's brain activity using positron emission tomography (PET)
scans. These were both performed by the other two principal authors of the
study, Drs. Andrew Feigin and David Eidelberg of North Shore-Long Island
Jewish Health System.
"Like all phase 1 studies, this one was primarily focused on gauging the
safety of the technique," Dr. Kaplitt says. "And on that count it succeeded
brilliantly: We saw no adverse events related to the treatment, no
immunological changes or infections over the year of the study, no imaging
evidence of toxicity whatsoever."
The results in terms of clinical and neurological efficacy were also
encouraging.
"In terms of the UPDRS scores measuring motor function, we observed
significant improvements in the 'off-state' phase -- meaning that period
when Parkinson's patients have been off their medicines for 12 hours -- and
also in the on-medication phase, when they were taking their drugs," Dr.
Kaplitt says.
For example, at three months post-treatment, the patients as a group had
already charted between a 25- and 30-percent improvement in off-state UPDRS
scores, and those improvements persisted over the full year of the study.
Similar results were seen in the on-medication state, the researchers found.
Several individual patients showed impressive improvements of between 40
percent and 65 percent.
"That was really surprising and heartening, because traditional Parkinson's
surgeries improve patients in the off-state but not as frequently in the
on-medication state," Dr. Kaplitt says.
"Interestingly, these improvements in motor function were due to the side of
the body controlled by the brain hemisphere that had received the
treatment," Dr. During notes. "Also, AAV tends to require several weeks to
maximize and stabilize production of a therapeutic gene, and in fact we did
not see significant clinical changes until more than 1 month after surgery.
These both further suggest that it was the gene therapy that was driving
their improvement."
There were also strong trends toward reductions in medication-linked
dyskinesia (movement difficulties) and improved activities of daily living,
although neither of these trends reached statistical significance.
Finally, PET scans revealed a more normal level of activity up to 1 year
following surgery in exactly those areas of the brain that the researchers
had been hoping to "fix." Again, this improvement "occurred only in that
half of the brain that had received the GAD gene," Dr. Eidelberg says.
Will these remarkable improvements persist" Only longer follow-up can tell,
but prior studies in animals, including primates, suggest that the
transplanted gene does stay active for years, Dr. Kaplitt says.
"Our next step of course is to move towards a larger, more definitive
efficacy-centered study," he notes.
"We believe that this breakthrough trial has implications that go far beyond
Parkinson's research," Dr. Kaplitt adds. "It's taken us nearly two decades
of hard work to get here, but the success of this trial lays the foundation
for the use of gene therapy against neurological diseases generally. We've
now shown that the genetic modification of the patient's own brain cells can
be done safely, and it appears to have enough effectiveness in this case to
justify further exploration -- potentially opening up gene therapy for a
host of brain disorders."

Rayilyn Brown
Board Member AZNPF
Arizona Chapter National Parkinson's Foundation
[log in to unmask]

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn