Gene Therapy Surgery Might Slow Alzheimer's
By Scott LaFee
UNION-TRIBUNE STAFF WRITER

April 28, 2004

An experimental surgical procedure that involves injecting genetically modified skin cells into the brains of patients
with Alzheimer's appears to significantly slow the disease's progression, a UCSD neurologist reported yesterday.

The findings, reported by Dr. Mark H. Tuszynski at a meeting of the American Academy of Neurology in San Francisco,
emerge from the 2112-year study involving eight patients diagnosed with early-stage Alzheimer's.

The study – the first to use human gene therapy to treat a neurological condition – represents the initial phase of
broader planned clinical trials. It was conducted by Tuszynski, Dr. Hoi Sang U, a UCSD neurosurgeon, Dr. Leon Thal,
director of the UCSD Alzheimer's Disease Research Center, and colleagues.

The principle purpose of the first phase is to assess the safety and toxicity of the gene therapy treatment. Six of the
patients, ages 59 to 78, suffered no ill effects and have resumed their lives. Two patients experienced bleeding in the
brain during their surgeries: One recovered quickly, but the other did not and died of a heart attack five weeks after
treatment.

"The gene therapy did not cause the heart attack," said Tuszynski of the deceased patient – a male in his 70s. "But I
think that the bleed, which kept him in the hospital, may have contributed to increased stress levels that culminated
in the attack."

While the first-phase study was not intended to broadly or deeply assess therapeutic value, Tuszynski said the gene
therapy treatment produced some encouraging data.

First, cognitive testing of the patients before and after treatment, using two common tests for evaluating mental
function, indicated a significant reduction in the rate of mental decline, an overall slowdown of roughly 50 percent.
As time passed, greater reductions in decline were recorded.

"If the effect of our treatment – and the numbers – hold up, I would say this approach represents a very significant
improvement over existing therapies. It doesn't cure Alzheimer's or stop the progression of the disease, but it may
substantially slow it down, which can have real-life benefits such as delaying entry into a nursing home," said
Tuszynski.

Second, UCSD researchers were able to compare the metabolic rates of two patients from PET scans taken before and after
treatment. In both patients, brain metabolism increased, an indication of greater cellular activity and possibly of
neuron growth.

Third, an autopsy of the patient who died revealed that brain cells exposed to the grafted genetic material grew new
extensions. "That response was surprising in that it occurred in just five weeks," said Tuszynski.

Daunting disease

Alzheimer's disease is a progressive neurological condition characterized by escalating brain-cell death and subsequent
loss of mental functions, such as memory and learning. It afflicts more than 4 million Americans, with estimates
projecting this figure to double within 20 years and triple by 2050. Currently, there is no cure or even an effective
treatment.

The UCSD study was based on earlier animal tests. In those experiments, published in 1999, Tuszynski, Fred Gage of The
Salk Institute and others reported that injecting additional nerve growth factor or NGF – a naturally occurring protein
– into the brains of rats and monkeys halted brain-cell death, sometimes dramatically. Monkeys that had suffered neuron
loss due to ordinary aging showed significant brain growth after being injected with NGF. Existing neurons re-
established lost connections, producing rejuvenated brains in treated monkeys that biologically mirrored their younger
counterparts.

The big question was whether a similar effect could be induced in humans. The first step was to make sure the surgical
procedure was safe and the gene therapy caused no harm. Essentially, the treatment worked like this:

Doctors extracted skin cells from each patient and genetically altered them in a laboratory to express human NGF, a
protein that serves as a kind of brain-cell stimulant.

The modified cells were then carefully injected through ultrathin needles deep into the brain, into a thumb-sized
region called the nucleus basalis of Meynert, which is broadly wired to the cortex and significantly involved in higher
cognitive functions such as memory and learning.

Injecting the modified cells, about two drops' worth, requires incredible precision, not only because the target areas
are small but also because the NGF does not migrate far from where it is infused – just one or two millimeters.

A millimeter is about the thickness of a nickel.

All eight patients were immobilized in a specially designed metal frame that fitted around and screwed into their
shaved heads, but the first few patients were only mildly sedated and remained awake so doctors could monitor their
mental function during the daylong operations.

In two of the surgeries, researchers say, patients moved while needles were still inside their brains, causing
bleeding. Tuszynski said in neither case was the amount of fluid sufficiently large to require surgeons to drain the
brain, but in the case of the patient who later died, cerebral clotting was enough to disable him.

Dead patient

A report by Tuszynski to the university's Human Research Protection Program said that the patient who later died
suffered two bleeds in the brain during his surgery, most likely due to patient movement and/or a bit of surgical glue
lacerating a blood vessel.

As a result of the bleeding episodes, UCSD researchers altered treatment protocol. To reduce the chance of inadvertent
movement, subsequent patients were completely anesthetized without complication, Tuszynski said. To reduce the risk of
bleeding in the brain, surgeons eliminated the use of fibrin glue and required that patients temporarily suspend use of
any drug that might affect the ability of blood to clot.

And they changed the patient consent form to better represent the risk of bleeding, from a 1 percent chance to a 20
percent chance.

Despite the death of one patient, Tuszynski believes the study has been a success.

"We learned three things," he said. "We can do the procedure safely with full anesthesia. We can deliver the NGF
safely. And that the gene therapy is safe. There were no adverse events related to the therapy at all."

Next steps

Plans for the second phase of the trial have begun, but they will not happen at UCSD. Instead, the second phase will be
conducted at the Rush University Alzheimer's Disease Center in Chicago.

Moving the second phase to a new city, Tuszynski said, will widen the pool of potential patients – the second phase may
involve 40 or more volunteers – and expose more doctors to the procedure. Tuszynski noted that there are also plans to
eventually add a third testing site on the East Coast.

In addition, Tuszynski is stepping back from the trial due to a conflict of interest. In the course of developing the
gene therapy, Tuszynski and others founded a biotechnology company – Ceregene – to develop and promote gene therapies
for neurological disorders including Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis.

The safety phase of the trial was funded by The Shiley Family Foundation and the Institute for the Study of Aging in
New York. The next phase will be funded by Ceregene, thus requiring an outside researcher to oversee testing.

There is one other change. Researchers have switched to a different vector or carrier of NGF, from modified skin cells
to an adeno-associated virus, a naturally occurring virus that is not known to cause disease in humans.

The virus, said Tuszynski, expresses NGF longer and farther and has already been used successfully in 24 clinical
trials, including three involving the brain.

Staff writer Cheryl Clark contributed to this story.

SOURCE: San Diego Union Tribune, CA
http://www.signonsandiego.com/news/science/20040428-9999-lz1c28alzheim.html

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