New approach to gene therapy may shrink brain tumors, prevent their spreadSeptember 26, 2008Massachusetts General Hospital (MGH) researchers are investigating a new approach to gene therapy for brain tumors - delivering a cancer-fighting gene to normal brain tissue around the tumor to keep it from spreading. An animal study published in the journal Molecular Therapy, the first to test the feasibility of such an approach, found that inducing mouse brain cells to secrete human interferon-beta suppressed and eliminated growth of human glioblastoma cells implanted nearby. "We had hypothesized that genetically engineering normal tissue surrounding a tumor could create a zone of resistance - a microenvironment that prevents the growth or spread of the tumor," says Miguel Sena-Esteves, PhD, of the MGH Neuroscience Center, the study's senior author. "This proof of principle study shows that this could be a highly effective approach, although there are many additional questions that need to be investigated." Glioblastoma is the most common and deadly form of brain tumor. Human clinical trials of other gene therapies have not significantly reduced tumor progression. One problem has been that patients' immune systems target the viral vectors used to deliver cancer-eliminating genes. Another issue has been inefficient gene delivery, due in part to the inherent cellular diversity found within an individual patient's tumor as well as among tumors from different patients. In addition, if tumor cells are successfully induced to express an anticancer protein, production of that protein will drop as the tumor dies, allowing any cells that did not receive the gene to resume growing. In the current study the MGH team examined whether expression of a therapeutic gene in normal brain cells could form a stable and effective anti-tumor reservoir. The researchers first pretreated immune-deficient mice by delivering a gene for human interferon-beta - a protein being tested against several types of cancer - into the animals' brains using adeno-associated virus vectors known to effectively deliver genes to neurons in the brain without the immune reaction produced by other vectors. Two weeks later, human glioblastoma cells were injected into the same or adjacent areas of the animal's brains. After only four days, mice expressing interferon-beta had significantly smaller tumors than did a control group pretreated with gene-free vector. Two weeks after the glioblastoma cells were introduced, the tumors had completely disappeared from the brains of the gene-therapy-treated mice. Several additional experiments verified that the anti-tumor effect was produced by expression of interferon-beta in normal tissue. The same tumor growth suppression was seen when the genes were delivered to one side of the brain and tumor cells were injected into the other. Using a specialized vector that allows genes to be expressed only in neuronal cells and not the glial cells from which glioblastomas originate also produced similar results. While other gene therapy studies that have induced tumor regression in mouse models required several vector injections, these experiments were able to suppress growth and eliminate the implanted tumor with a single injection of the interferon-beta-encoding vector, underscoring the approach's effectiveness. "These results are particularly important as we build on our understanding of the microenvironments that allow tumors to grow and spread," explains Sena-Esteves, an assistant professor of Neurology at Harvard Medical School. "The therapeutic principle of genetically engineering normal brain tissue could be used to manipulate proteins required for that microenvironment, preventing tumors from migrating within the patients brain and escaping other therapies." The same zone-of-resistance approach could also be applied to the treatment of other solid tumors, he notes. Since interferon-beta treatment is known to have side effects, it will be important to identify any toxicity caused by long term secretion of the protein in the brain and develop preventive strategies, such as turning off the introduced genes. Next the MGH team is planning to test this strategy on glioblastomas that occur naturally in dogs, which could not only generate additional data supporting human trials but also develop veterinary treatments for canine patients. Massachusetts General Hospital |
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| Related Gene Therapy Current Events and Gene Therapy News Articles Research reveals lipids' unexpected role in triggering death of brain cells The lipid that accumulates in brain cells of individuals with an inherited enzyme disorder also drives the cell death that is a hallmark of the disease, according to new research led by St. Jude Children's Research Hospital investigators. No-entry zones for AIDS virus The AIDS virus inserts its genetic material into the genome of the infected cell. Scientists of the German Cancer Research Center have now shown for the first time that the virus almost entirely spares particular sites in the human genetic material in this process. This finding may be useful for developing new, specific AIDS drugs. Cornell researchers identify a weak link in cancer cell armor The seeming invincibility of cancerous tumors may be crumbling, thanks to a promising new gene therapy that eliminates the ability of certain cells to repair themselves. Treatment to improve degenerating muscle gains strength A study appearing in Science Translational Medicine puts scientists one step closer to clinical trials to test a gene delivery strategy to improve muscle mass and function in patients with certain degenerative muscle disorders. Iowa State University researcher discovers key to vital DNA, protein interaction A researcher at Iowa State University has discovered how a group of proteins from plant pathogenic bacteria interact with DNA in the plant cell, opening up the possibility for what the scientist calls a "cascade of advances." Scientists successfully reprogram blood cells Researchers have transplanted genetically modified hematopoietic stem cells into mice so that their developing red blood cells produce a critical lysosomal enzyme -preventing or reducing organ and central nervous system damage from the often-fatal genetic disorder Hurler's syndrome. Immune therapy can protect against or treat later lymphoma Specially developed immune system cells that target the common Epstein-Barr virus can protect immune-suppressed bone marrow transplant recipients against lymph system disease and cancers that arise from the viral infection. Caltech researchers show efficacy of gene therapy in mouse models of Huntington's disease Researchers at the California Institute of Technology (Caltech) have shown that a highly specific intrabody (an antibody fragment that works against a target inside a cell) is capable of stalling the development of Huntington's disease in a variety of mouse models. Immunotherapy demonstrates long-term success in treating lymphoma Targeted immunotherapy has been an attractive new therapeutic area for a number of cancers because it has the potential to destroy tumor cells without damaging surrounding normal tissue. New study results demonstrate high success rates using specialized white blood cells to prevent or treat lymphoma associated with the Epstein-Barr virus (EBV-lymphoma) in patients who have received a hematopoietic stem cell transplant (HSCT). Toward bold new anti-cancer medicines Bold new strategies in the battle against cancer may turn forms of the disease that presently are incurable into manageable conditions that can be controlled for long periods of time. More Gene Therapy Current Events and Gene Therapy News Articles |
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