Sunday, October 14, 2001
How
a hole in the head made medical history
By Judy Siegel-Itzkovich
Gene therapy has been tried on three American Jewish
children suffering from the incurable Canavan disease - and the signs
so far are promising.
Gene therapy, in which a healthy gene is inserted into
the body via a real or synthetic virus or other vector to proliferate
into the DNA and repair a serious and usually fatal genetic defect,
has had few successes in recent years.
It has been used effectively to release "bubble babies"
- born with such ineffective immune systems that they had to be isolated
from all human contact - from their sealed plastic enclosures. But other
diseases have not responded well, mainly because the tiny organism meant
to transfer the healthy gene to the cells has not been very effective.
But now the technique has been tried on three American
Jewish children suffering from the incurable genetic disorder Canavan
disease. And while it will take a year or so to know for sure whether
it is effective, the signs so far are promising.
The pioneering operations, in which holes are drilled in
the skull and the replacement genes inserted into the brain, were performed
this summer at Jefferson Medical College Hospital in Philadelphia.
During the first three-hour operation performed in June,
neurosurgeon Dr. Andrew Freese cut six small holes into the skull of
Lindsay Karlin. Through hair-thin catheters he then infused areas of
her brain with 90 billion synthetic virus particles meant to infect
neurons and express a normal human gene that she lacks.
The surgeons made medical history, as the young patient
became the first person in the world to have recombinant viruses injected
into the brain to treat an illness other than cancer.
By mid-July, two other children had undergone an operation
like Lindsay's, and researchers examined them a month later.
Doctors report that they all improved on various neurological
and psychometric measures.
Lindsay, for example, showed an increased interest in her
surroundings, and she vocalized and moved her hands more. All the neurologists
and physiotherapists were amazed, the hospital reported.
The Canavan trial signals a new phase in a 10-year offensive
that gene therapy researchers have waged against neurodegenerative disorders.
Previously limited mostly to cell-culture and animal experiments, the
scientists are now starting to take their protocols and reagents to
the clinic.
Freese hopes to test the therapy on a total of 15 children
in the coming year.
Canavan disease, named for Myrtelle Canavan, the researcher
who first described the disease in 1931, is caused by the lack of an
enzyme called aspartoacylase (ASPA). This enzyme is normally found in
the part of the brain where nerve impulses are sent to other parts of
the brain and to the spinal cord, says Prof. Orly Elpeleg, a pediatrician
and director of the metabolic diseases unit at Jerusalem's Shaare Zedek.
ASPA breaks down a compound called NAA into two smaller
compounds. When ASPA is missing from the body, NAA accumulates and causes
brain damage, mental retardation, tremors, an oversized head and paralysis.
Canavan disease may also lead to blindness, due to problems
with nerves from the eye, feeding difficulties, poor weight gain and
problems with swallowing.
The earliest symptoms usually occur between three and five
months of age. The lack of head control is often one of the first signs
noticed; such infants are described as "floppy."
Learning problems usually begin within the first nine months
of life. Later the child may be unable to perform such tasks as rolling
over or grasping objects and become inattentive. but eventually the
child's muscles become tense and stiff.
The severity varies, with most patients dying before the
age of five and some surviving into their second, third or even fourth
decade.
The defective gene for Canavan is carried by one out of
every 40 to 50 Ashkenazi Jews; it is thus almost as common as the gene
for Tay-Sachs. Canavan also occurs also in a very small number of non-Jews
of various ethnic backgrounds, but the mutation is different.
There have been three new diagnosed cases in Israel in
the last three years. Between 200 and 300 children and youngsters in
the US have the disease.
Carriers can pass it on to their children, but they themselves
do not suffer from the condition. It can be identified in a carrier
by a genetic test and and diagnosed in a patient or the defective gene
with a blood test measuring levels of ASPA.
Prof. Gideon Bach, head of the genetics department at Hadassah-University
Hospital in Jerusalem's Ein Kerem, adds that it would take about a year
of observation to know for certain whether the gene therapy could be
pronounced a success. The process is very complicated, he explained,
because of the blood-brain barrier that prevents substances from passing
from the bloodstream into the brain.
In another genetic disease in which a vital enzyme is missing,
such as Gaucher's disease, one could theoretically perform a genetic
correction by introducing vectors such as viruses in the body's internal
organs. "But for brain diseases it is not clear if there can be
significant reverse in neurological damage."
Prof. Eithan Galun, director of the Goldyne Savad Institute
of Gene Therapy at Hadassah-University Hospital in Jerusalem's Ein Kerem,
says the Jefferson Medical College trial is "very important"
and that he hopes there will be very positive results.
Unlike many genetic disorders, he explains, Canavan affects
only the central nervous system; the involved gene had just been cloned
and its protein product had a straightforward function; and gene-therapy
efficacy could be gauged by measuring NAA levels in the brain through
spectroscopy.
Elpeleg notes that the number of babies born with Canavan
disease here has dropped dramatically in recent years, largely due to
voluntary screening undergone by haredi couples before they decide to
marry, and on non-haredi Ashkenazi couples who undergo genetic tests
before their first baby is born; the test for Canavan's, as well as
other genetic diseases, is not included in the basket of health services.
If no screening were available, about 10 such infants would be born
here each year.
The frequency of carriers for Tay-Sachs disease, which
also involves Ashkenazi Jews and is fatal, is twice as high as Canavan's.
Elpeleg said that the Philadelphia hospital offered the
experimental gene therapy to a handful of Israeli children, but families
were deterred by the fact that it was so invasive, required very expensive
monitoring in the US not covered by health funds, and because children
with more advanced neurological symptoms do not suffer because they
are suspended in a vegetative state.
"But I know of some patients who have reached their
teens and even 20," Elpeleg said.
"I expect the therapy will have some positive effect,
but that doesn't mean it will be a cure or reverse existing damage,"
says Elpeleg. "Patients must carefully selected for the trials,
as by the time the disease is diagnosed by symptoms, serious neurological
damage has already set in. But we welcome all such innovative work."
The second child identified as having undergone the gene
therapy technique is Max Randell, son of Ilyce and Michael Randell of
Rolling Hills, Illinois, who established the Canavan Research-Ilinois
Foundation to promote research into the disorder.
The parents hope the treatment will slow the relentless
decline in the condition of their three-and-a-half-year-old, blond,
blue-eyed son, who is mentally alert but never learned to turn over,
crawl or talk - locked, the Randells say, in a body he can barely move.
They raised $65,000 to get Max included in the trial. The
toddler was put under general anesthesia and had six holes drilled into
his skull. An optical fiber was used to slowly introduce the virus solution
into his brain.
Seeing her son with his head shaved made Ilyce think of
the day he was born. "I mean, he's huge now," she said in
an interview. "But in a way this does represent a new start."
Since it was carried out, they say, Max has "showed
signs of improvement, he's more alert and able to track people with
his eyes."
The couple told reporters they were looking forward to
a second treatment soon using a real virus instead of the synthetic
one used initially.
Israeli geneticists doing research and clinical work on
Canavan-at Soroka, Ichilov, Bnai Zion and Hadassah-University Hospitals
- are intensely interested in the results of the experimental treatment,
which, if it benefits the patients, will surely be tried here.
© 2001 The Jerusalem Post
