Gene Therapy Reduces Amyloid Plaques In Mice With Model Of Alzheimer Disease

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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