NEW LOOK AT ALZHEIMER DISEASE VACCINE

Trials of a promising new therapy for Alzheimer disease were abruptly halted this year when several of the 360-some patients enrolled developed inflammation in the brain. But two new studies in Nature Medicine raise the possibility that, with modifications, the basic approach may still effectively counteract Alzheimer disease. One of the studies provides the first data on the patients themselves. The patients in the trials were treated with a vaccine designed to clear the tangles of amyloid-beta (A-beta) protein, called plaques, that accumulate in the brains of Alzheimer's patients. The researchers, with the pharmaceutical company Elan and its corporate partner, American Home Products, had reason to believe this approach would work. Previous data had indicated that in mice, the vaccine resulted in antibodies directed against A-beta, cleared the plaques and reversed symptoms of neurodegeneration. Furthermore, a phase 1 trial for safety was completed successfully in the year 2000. Now, Roger Nitsch and colleagues at the University of Zürich present evidence that the human patients actually did accumulate antibodies against A-beta, which is a critical step in plaque clearance. The antibodies recognized only A-beta in tangles, diffuse A-beta deposits and A-beta in blood vessels of the brain. In these patients, the antibodies are able to cross the blood-brain barrier, which suggests they might have the capacity to directly destroy plaques in the brain. Notably, the antibodies did not cross-react with a longer form of A-beta that occurs in the nerve cells of healthy people as well as Alzheimer's patients. The function of that non-aggregated form is unknown, but healthy nerve cells can contain a lot of it. This selectivity is good news, since an attack on the longer form of A-beta could potentially result in autoimmune disease or other complications. The results suggest that the vaccine selectively targets the disease-associated form of A-beta and holds out promise for the vaccine approach. In a second study, researchers in Toronto and Konstanz, Germany took a closer look at the A-beta vaccine in mice. The researchers provide evidence that in mice, the vaccine-generated antibodies against A-beta might work by sequestering A-beta from plaques. The researchers found that the vaccine worked effectively if mice were injected with only a small portion of A-beta (less than 10 amino acids in length). That raises a possibility that a more refined vaccine, such as this, could bypass the inflammatory side effects in humans. The findings also open the door to generating small-molecule drugs that mimic the effects of the vaccine. TUMOR VACCINE TARGETS NEW BLOOD VESSELS Researchers have engineered an oral vaccine that counteracts cancer in mice by choking the blood supply to tumors. The DNA-based vaccine, developed by Ralph Reisfeld at the Scripps Research Institute in La Jolla, California, and colleagues is described in the December issue of Nature Medicine. Tumors need a blood supply to survive once they get more than a couple millimeters in size. This fact has propelled a great deal of interest in the design of treatments that prevent infusion of blood vessels into tumors. Such an approach also has the advantage of being potentially effective against a wide range of tumor types. In this study, the investigators targeted a protein produced in new blood vessels, called vascular endothelial growth factor receptor 2 or FLK-1. To target FLK-1, the authors engineered DNA encoding the FLK-1 protein into a non-infectious strain of the bacterium S. typhimurium, and administered this live vaccine into mice. Animals treated with the FLK-1 vaccine showed reduced vessel growth and were able to fend off tumors in models of three different types of cancer. The vaccine induced no ill effects by several measures, including fertility. But the mice did have a slight delay in wound healing, consistent with the involvement of new vessel growth in this process. Many current approaches to shutting off tumor blood supply rely on specific inhibitors that often require constant administration at relatively high doses. The FLK-1 vaccine, in contrast, protected mice even 10 months after their last dose. Moreover, DNA vaccines based on other proteins are already being tested in clinical trials. Whether a FLK-1 vaccine could work in humans remains to be seen, but could be particularly effective in combination with treatments that promote cell death or affect other aspects of tumorigenesis. Such a vaccine has the greatest potential in preventing or delaying the onset of recurrent malignancies, especially in cases of minimal residual disease after other treatments.

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