 Alzheimer's Cognitive Decline Slowed In Gene Therapy Patients
By
Sue Pondrom I April 25,
2005
Patients with Alzheimer's disease who received injections of genetically altered cells into their brains appeared to show a reduced rate of cognitive decline and increased metabolic activity in the brain, according to a study published in yesterday's issue of the online journal Nature Medicine.
PET
scans demonstrated an
increase in the brain's
use of glucose, an indication
of increased brain activity,
while mental-status tests
showed the patients' rate
of cognitive decline was
reduced by 36 to 51 percent.
In addition, researchers
examined the brain tissue
of a study participant
who had died and found
robust growth of extensions
from the dying cholinergic
cells near the site of
growth factor gene delivery.
Cholinergic neuron loss
is a cardinal feature
of Alzheimer's disease,
a progressive brain disorder
affecting memory, learning,
attention and other cognitive
processes.
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| In the MRI suite, Hoi Sang U and Mark Tuszynski discuss the brain coordinates for the tissue implants with members of the surgical team. |
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"If
validated in further clinical
trials, this would represent
a substantially more effective
therapy than current treatments
for Alzheimer's disease,"
said Dr. Mark Tuszynski,
a UCSD professor of neurosciences
and neurologist with the
VA San Diego Healthcare
System who served as the
study's principal investigator.
"This would also represent
the first therapy for
a human neurological disease
that acts by preventing
cell death."
In this first-ever gene therapy for Alzheimer's disease, UCSD physician-scientists took skin cells from eight patients diagnosed with early Alzheimer's disease. The tissue was modified in the lab to express nerve growth factor (NGF), a naturally occurring protein that prevents cell death and stimulates cell function. In surgeries that took place in 2001 and 2002 at UCSD's John M. and Sally B. Thornton Hospital, the genetically modified tissue was implanted deep within the brains of the eight patients who had volunteered for the study.
The
human clinical trial was
undertaken following extensive
studies in primates conducted
by Tuszynski and colleagues,
which showed that grafting
NGF-producing tissue into
the brains of aged monkeys
restored atrophied brain
cells to near-normal size
and quantity, and also
restored axons connecting
the brain cells, essential
for communication between
cells. The recent human
studies were a Phase I
clinical trial, designed
to test safety and toxicity.
The procedure was initially
performed while patients
were awake but lightly
sedated, and two patients
moved as the cells were
being injected, resulting
in bleeding in the brain.
One of these patients
died five weeks later.
As a result of the bleeds,
the protocol was redesigned
to perform the procedure
under general anesthesia
and all subsequent procedures
were performed without
complication.
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| Averaged FDG PET scan images in four subjects treated with NGF, overlaid on standardized MRI templates. Representative axial sections, with 6-8 months between first and second scan, showing widespread interval increases in brain metabolism. Flame scale indicates FDG use /100g tissue/min; red color indicates more FDG use than blue. |
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Cognitive outcomes were assessed in the six patients who completed the NGF delivery procedure safely. The Mini Mental Status Examination (MMSE), which evaluates cognitive function, was administered at screening, the time of treatment and at several intervals after treatment. Over an average post-treatment follow-up period of 22 months, the rate of decline on the MMSE among NGF-treated patients was reduced by as much as 51 percent. An additional test, called the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent, or ADAS-Cog, also showed improvements in rates of decline followed the MMSE findings.
Post-operative PET scans in four subjects showed significant increases in the brain's absorption of a radioisotope called 18-fluorodeoxyglucose, an indicator of increased metabolic activity in the brain. The researchers noted that the increase was observed in most cortical regions that receive cholinergic input from forebrain nerve cells called the nucleus basalis, and in the cerebellum, a structure associated with cortical plasticity.
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Dr. Hoi Sang U developed special instruments for the procedure. |
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In addition to Tuszynski, authors of the paper in Nature Medicine, were Dr. Leon Thal, UCSD chair of neurosciences, director of the UCSD Shiley-Marcos Alzheimer's Disease Research Center (ADRC), and a neurologist with the VA San Diego Healthcare System; Mary Margaret Pay., R.N., David P. Salmon, Armin Blesch, Dr. Gilbert Ho, Dr. Gang Tong, Dr. Lawrence Hansen, and James Conner, of the UCSD Department of Neurosciences; Dr. Hoi Sang U, UCSD Department of Surgery; Lee Vahlsing, UCSD Department of Neurosciences and VA San Diego Healthcare System; Dr. Roy Bakay, Rush University Department of Surgery; Dr. Piyush Patel, UCSD Department of Anesthesiology; Dr. Steven G. Potkin, and Christine Gall, UC Irvine Department of Neurology; James Fallon, UC Irvine Department of Neurobiology; Elliott J. Mufson, and Jeffrey H. Kordower, Rush University Department of Neurosciences.
The study was supported by the Institute for the Study of Aging and the Shiley Family Foundation.
Based on the positive findings of this Phase I trial, a new Phase I/II study using direct NGF gene delivery to the brain, thereby eliminating the need for grafting cells, is currently underway at Rush University Medical Center in Chicago, sponsored by the San Diego biotechnology company Ceregene, Inc. The Chicago trial is under the direction of Dr. David Bennett, director of the Rush University Alzheimer's Disease Center, and Dr. Zoe Arvanitakis, a Rush neurologist.
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