Treatment Cures Alzheimer’s Disease In Mice
A trial of antibody therapy against human prion disease is moving forward, John Collinge, MD, professor of neurology and head of the department of neurodegenerative disease at the University College London Institute of Neurology, reported during his presentation. Dr. Collinge has shown that variant Creutzfeldt-Jakob disease (vCJD) was due to the same strain of prion that caused bovine spongiform encephalopathy, and has been a leader in deepening the understanding of human prion diseases.
The antibody trial is based on the now well-accepted mechanism of prion propagation by templated misfolding of normal prion protein. The conformation change, from alpha helix to beta sheet, thus creates new seeds that can trigger more misfolding, spreading the infection. Antibodies against the misfolded protein are designed to bind to the misfolded form, sequestering it and preventing it from interacting with normal protein. Because the protein is eventually cleared from the cells, Dr. Collinge said, “if you take the concentration of misfolded protein low enough, you ought to be able to cure the infection.” That has been accomplished in mice, which live into old age rather than die within months. “We can find no prions in them at all. They are effectively cured.”
Those results have laid the groundwork for a first-in-human trial of an antibody, PRN100, in patients with the most aggressive form of vCJD. The initial plan is to give the antibody intravenously, Dr. Collinge said, recognizing that the blood-brain barrier is quite leaky in these patients. If that fails to produce adequate antibody levels in the brain, intraventricular administration is an alternative. Early diagnosis will be critical, Dr. George noted, since the disease course runs so quickly, “but this could be a game-changer for the prion diseases.”
Dr. Collinge said that there may be some utility for targeting prions in Alzheimer’s disease, given the evidence that prions may mediate the effect of a-beta on neuronal plasticity. In rats, anti-prion antibody administration can block the deleterious cognitive effects of Alzheimer’s tissue extracts.
“There is now real evidence of the potential transmissibility of Alzheimer’s,” says Thomas Wiesniewski M.D. a prion and Alzheimer’s researcher at New York University School of Medicine. “In fact, this ability to transmit an abnormal conformation is probably a universal property of amyloid-forming proteins (prions).”
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