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Dec 1, 2009 (Vol. 29, No. 21)

Neuroscience Benefits from Cash Infusion

NIH Commits $30 Million to Mapping Circuitry of the Brain Using Imaging Technologies

  • Breaking Down Barriers

    Click Image To Enlarge +
    Dual-channel fluorescence image of F-actin and nuclei distribution in bovine pulmonary artery endothelial cells obtained with Thorlabs’ Video-rate Confocal System.

    The blood brain barrier (BBB), which regulates the passage of compounds into and out of the brain by relying on tightly controlled cellular junctions, is essential for the normal functioning of the central nervous system. However, it presents a significant challenge for therapeutic drug delivery to the brain and inhibits the body’s ability to eliminate unwanted molecules that may build up in the brain as a result of disease.

    Jean-Paul Castaigne, M.D., president and CEO of Angiochem, highlighted the large unmet medical need in the treatment of brain diseases, with the overall market estimated at >$65 billion, broken down into psychiatric disorders ($19.1 billion), Alzheimer’s disease ($6.4 billion), other neurodegenerative diseases ($10.7 billion), and brain cancer ($1.6 billion).

    Angiochem designed its EPiC platform to develop drugs that target receptors present on cells that actively transport molecules across the BBB, such as low density lipoprotein (LDL) receptor-related protein (LRP). LRP is noteworthy for its ability to transport amyloid beta from the brain to the bloodstream. The company currently has an LRP-mediated taxane compound—a DNA replication inhibitor—to treat glioma, a highly malignant form of brain cancer, in Phase II trials. Other EPiC therapeutics are in preclinical development for the treatment of neurodegenerative diseases and obesity, and for neuroprotection in hypothermia.

    Jan Drappatz, M.D., from the Dana-Farber Cancer Institute, presented data gathered from the more than 100 patients with recurrent glioma treated with the drug in two Phase I/II escalating-dose studies. He reported no evidence of CNS toxicity or immunogenicity after repeated dosing, as well as early findings of efficacy, with evidence of disease control in 60% of patients with primary brain cancer who received a therapeutic dose, and in 71% of patients with secondary (metastatic) brain cancer.

    These encouraging results were supported by reductions in brain tumor size and reversal of neurological decline in several cases, and by substantial reductions in the size of metastatic tumors in a variety of other organs. Therapeutic concentrations of the drug were documented in brain tumor tissue removed from patients, demonstrating its ability to cross the BBB.

    Berislav Zlokovic, M.D., Ph.D., from the University of Rochester, discussed the role of the BBB in the pathogenesis of Alzheimer’s disease (AD) and described a strategy for engineering a mutant form of the LRP1 receptor that could pull amyloid beta from the brains of affected patients.

    In other work, Serge Rivest, Ph.D., from University Laval in Quebec, demonstrated that bone marrow-derived microglial cells—the main type of immune cell in the central nervous system—are present in the blood and are able to cross the BBB. In a mouse model of AD, these cells can associate with amyloid protein in the brain and prevent the formation of amyloid deposits, or eliminate those already present. He proposed the use of autologous microglial cells derived from bone marrow stem cells as a vehicle for gene therapy to treat AD.

    John El Khoury, Ph.D., from Harvard Medical School, pointed out that the role of microglia in AD pathogenesis is not yet clear, with some evidence suggesting a protective effect and the ability to clear amyloid, while other data suggests a detrimental role. At the root of this mechanism is the interaction between the microglial cell and amyloid, and the process by which the protein alters microglial function and stimulates cytokine and chemokine production that compromises neuronal viability.

    Kate Nautiyal, Ph.D., from Columbia University, showed a link between another type of immune cell, the mast cell, which mediates allergic and anaphylactic responses, to regulation of emotion and cognition. Mast cells can be found in the hippocampus and are able to cross the BBB. They appear to have a role in easing anxiety and promoting learning and may represent a novel target for treating mental health disorders.

    In a symposium exploring the role of the BBB in neurodegeneration, presenters gave examples of BBB dysfunction in a variety of acute and chronic disorders, including stroke, dementia, Parkinson’s disease, and amyotrophic lateral sclerosis. This dysfunction may result in abnormal entry of molecules into the brain or insufficient clearance of toxic molecules. Research findings have demonstrated that altered blood flow resulting from diminished microcirculation in various brain regions likely precedes neuronal changes and clinical symptoms. Dramatic reductions in capillary volume have been demonstrated in mice before neurodegenerative changes occur, and the total brain capillary length is reduced in AD, for example. This neurovascular uncoupling appears to compromise the BBB and may prove to be a fruitful target for drug discovery.

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