How a hole in the head made medical history

[Max]

How a hole in the head made medical history
By Judy Siegel-Itzkovich
(October 14) - 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.




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Maksim (Max) Bily
mail to : imax@odyssee.net
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