A new gene therapy technique has been shown to reduce the amount of amyloid-beta protein (which forms the plaques found in the brains of people with Alzheimer’s disease) in the brains of mice. In a paper published this week in the open access medical journal PLoS Medicine Matthew Hemming, Dennis Selkoe and colleagues from Harvard Medical School generated a secreted form of neprilysin, a protease that can break down amyloid-beta protein, and used primary fibroblasts to introduce this soluble protease into the brains of mice who had advanced plaque deposition.
The pathologic hallmarks of Alzheimer disease are extracellular plaques of amyloid-beta protein and intraneuronal neurofibrillary tangles of tau protein, both of which accumulate in the regions of the brain that mediate memory and thought. Current treatments for Alzheimer disease affect only the symptoms. Ultimately it is to be hoped that it would be possible to develop disease-modifying interventions that would lower the production of amyloid-beta protein or enhance its clearance.
The authors found that on examination of the brains after implantation of modified fibroblasts there was significant reduction of amyloid-beta protein plaques at the site of engraftment, as well as in two sites distal to the implantation site. Although these results are encouraging and suggest that this technique might have potential for therapy, much further work would need to be done before it was clear whether it might work in humans. For example, it would need to be shown that the techniques used were safe in humans, and that in addition the clearance of the plaques actually improved the symptoms that the plaques cause. One approach that stems directly from this work is attempting to implant the neprilysin-secreting cells in a peripheral location (e.g., under the skin) to learn whether systemic elevation of secreted neprilysin (or another amyloid-beta-degrading protease) might adequately decrease plaques in the brain.
Citation: Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, et al. (2007) Reducing amyloid plaque burden via ex vivo gene delivery of an Ab-degrading protease: A novel therapeutic approach to Alzheimer disease.
PLoS Med 4(8): e262.
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