Institutions in Israel putting gene therapy to work

JERUSALEM — Forty years since research into gene therapy began, more than 2,000 people have received treatment. But while many have been significantly helped, none has been permanently cured.

As a result, a worldwide biomedical effort is under way to make gene therapy viable — and Israel, with its treasure-house of ethnic groups, is an important player.

"There's no doubt gene therapy will work," says Dr. Michal Roll, research and development director at the Hadassah-Hebrew University Medical Center in Jerusalem. "The ideas are there. As we unravel more of the basic biology, we'll learn to construct healthy genes, get them to the right place, keep them there, get them working and, if necessary, shut them off."

Early optimism that this would be simple, however, has long since faded. Finding genes and their faults has been likened by Dr. Francis Collins of the National Institutes of Health to "searching for a burned-out light bulb in a house somewhere between the East and West coasts of North America, without knowing the state, much less the town or street the house is on."

And that's only the first hurdle. Nature throws up highly effective biological blocks to the critical second stage: getting healthy gene snippets to a precise target cell or organ, where they must work in the right way.

Scaling these hurdles is a worldwide endeavor, spurred by the Human Genome Project, the monumental $3 billion, 15-year effort launched by the United States in 1989 to find, identify and decipher the structure of each of our 100,000 genes. It's an endeavor in which Israeli researchers have made a special contribution.

"Israel's population constitutes a rich human laboratory for molecular geneticists, because it's far easier to trace genetic anomalies in inbred groups with homogenous pedigrees, such as Yemenite and Moroccan Jews, Druze and Arabs," says Professor Nadine Cohen-Elbaz, head of the Tamkin Molecular Human Genetics Research Facility at the Technion Institute of Technology in Haifa. "One current Technion project is a joint venture with GENSET in Paris, analyzing human genes to find links with common diseases, aiming to develop drugs to cure them. Another is a study of genetic anomalies among Israel's Arab population, where first-cousin marriages are common and genetic diseases are found in 40 percent of them."

Even when a gene is identified, however, its defects are hard to find. A complex gene, like that responsible for cystic fibrosis, can go wrong in hundreds of different places. In Israel's rich and varied gene-pool, researchers are tracking down faulty genes and seeing why they go wrong.

Professor Orly Reiner at the Weizmann Institute of Science in Rehovot, for example, has cloned and identified a gene responsible for lissencephaly, a severe mental retardation that occurs in one of every 30,000 live births.

Not all mutations, however, carry the same risk. Cohen-Elbaz is leading a multidisciplinary study of degrees of risk associated with different misprints in the familial breast cancer gene. Targeting high-risk Israeli Ashkenazi women — among whom breast cancer is 50 percent more common than in Israeli Arab women –Cohen-Elbaz is working with other health professionals, reviewing family medical histories, diet and lifestyle. The goal is to build an effective prevention program.

Where prevention fails, the aim is cure, and a key to gene therapy cure is getting the repaired gene to the right place. "Genes can't be injected," says Professor Ariella Oppenheim of Hadassah's hematology department. "They need special delivery vehicles."

One of the more promising such vehicles is the virus, an organism that can insert itself into cells. To become gene therapy's delivery boys, however, viruses must be stripped of their harmful qualities. Oppenheim is working with a virus from monkey kidney cells (SV40), which has a special affinity with bone marrow. She's hoping to make it a harmless envelope for healthy genes to repair defects resulting in crippling blood disorders, such as sickle-cell anemia.

The delivery vehicles aren't yet ready, but scientists are working on what they'll carry. Dr. Riad Agbaria of the Ben-Gurion University of the Negev is developing a cancer protocol in collaboration with the NIH. The aim is to insert a gene that produces enzymes that combine with a non-toxic drug, to make it lethal to tumor cells.

It's only a matter of time, it seems, before gene therapy fully arrives. When it comes, Israel will be ready with a $10 million National Center for Molecular Medicine and Gene Therapy, opened at Hadassah in November. At the center, ideas can be generated, evaluated and tested in the laboratory, then progress through animal studies into an FDA-level lab where gene-based medications are tailored to the needs of individual adult and pediatric patients.

Clinical practice is not the final chapter, says center head, Professor Eitan Galun. "New medications must flow on to further research and development. We must monitor every step. If the protocol works, we must know why. If it doesn't, why not. It's a different kind of medicine from knowing aspirin reduces pain and fever without needing to know why."