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First Public Conference Gene Therapy for Brain Tumors Using Herpes Virus Vectors Speaker Dr. Breakefield described experimental approaches to glioblastoma therapy that rely on novel vectors derived from herpes virus. These vectors can deliver genes that make brain tumor cells vulnerable to chemotherapy that has previously been powerless against them. She and her colleagues developed these vectors at Mass. General Hosp., where Dr. Breakefield has also been instrumental in discovering genes responsible for several neurologic disorders. She is a geneticist in the Molecular Neurogenetics Unit at MGH and a professor of neurology at HMS. One of Dr. Breakefield's vectors is now being tested in Phase I clinical trials. Topic One reason that brain tumors are notoriously difficult to treat is that the blood-brain barrier shuts out many anticancer drugs. Another is that brain tumor cells donāt divide as they travel from the primary mass to other parts of the brain, which makes them invisible to drugs that recognize and destroy only rapidly dividing cells. Dr. Breakefield's laboratory seeks to overcome these problems with an assortment of live vectors derived from the herpes simplex virus type 1, a common virus best known as the cause of cold sores. The purpose of these vectors is to track down tumor cells and destroy them by delivering a payload of genes. These genes make proteins that either kill the cells directly or make them susceptible to chemotherapy. Herpes virus is a good platform because it enters human cells readily, is big enough to carry numerous transgenes, and easily threads its genetic material into the hostās nuclear DNA. The downside is that herpes virus can cause encephalitis if it replicates freely in the brain. To keep this from happening, the investigators have developed a recombinant "replication conditional" virus that can copy itself only in dividing cells. Cancer-fighting genes are packaged in this recombinant vector and injected into primary tumor sites in the brains of rats and mice. Each vector is equipped with genes that make it impossible for the virus to replicate except in dividing cells, and with a marker gene that makes it possible to see which cells have been penetrated by the vector. The payload of therapeutic transgenes varies from one construct to the next: some vectors bear toxin genes that kill tumor cells directly, others code for an enzyme that cause the cells to produce toxins that can kill neighboring tumor cells. When the researchers administered these vectors to rats with a type of brain cancer that uniformly kills untreated animals, 50% of the treated animals survived. Dr. Breakefield cautioned, however, that these tumors are easier to destroy than human glioblastomas. The next challenge is to develop vectors that roam the parenchyma, intercepting migrating cancer cells and attacking new tumor foci. Dr. Breakefield is experimenting with a type of migratory brain cell, known as neural progenitor or C17 cells, developed by Evan Snyder, an assistant professor of neurology at Harvard Medical School. After a number of attempts, Dr. Breakefield and her colleagues have successfully used a vector to insert a marker gene into these cells. This marker is invisible until the C17 cells have migrated away from the original tumor site and into the parenchyma, then it becomes apparent. Next she would like to load these cells with delayed activation vectors that would hunt down migrant cancer cells and signal them to divide, thus making them vulnerable to chemotherapy. A Phase I clinical trial is already underway with replication conditional vectors bearing therapeutic transgenes. This is the first step toward what Dr. Breakefield hopes will someday be a standard approach to human brain tumors. If all goes well, she foresees a time when the primary mass will be removed and the cavity injected with vectors programmed to carry out various missions. Some will kill tumor cells outright, while others will disseminate into the brain, lighting up migratory cancer cells and delivering drugs or activation enzymes to tiny tumors in distant parts of the brain.
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