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.
Prion disease also is known as transmissible spongiform encephalopathy (TSE). The operative word is “transmissible.” Nobel Laureate Dr. Stanley Prusiner claims that all forms of TSE are caused by infectious prions.
“Alzheimer’s disease (AD) is the most common neurodegenerative disease in humans and will pose a considerable challenge to healthcare systems in the coming years,” Prusiner said. Aggregation of the β-amyloid (Aβ) peptide within the brain is thought to be an initiating event in AD pathogenesis. Many recent studies in transgenic mice have provided evidence that Aβ aggregates become self-propagating (infectious) during disease, leading to a cascade of protein aggregation in the brain, which may underlie the progressive nature of AD. The ability to self-propagate and the existence of distinct strains reveals that Aβ aggregates exhibit many properties indistinguishable from those of prions composed of PrPSc proteins. The evidence that Aβ can become a prion during disease, Aβ prions may be important for understanding the pathobiology of AD.”
Like prion diseases, misfolded alpha-synuclein and tau protein associated with Parkinson’s disease and Alzheimer’s disease, respectively, have been reported in skin tissues of patients with these conditions. Skin could serve as a screen for early diagnosis, but also for monitoring the accumulation of the misfolded proteins in the brain of these neurodegenerative diseases. It also could be another pathway of transmission.
“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).”
Crossbow Communications specializes in issue management and public affairs. Alzheimer’s disease, Creutzfeldt-Jakob disease and the prion disease epidemic is one of our special areas of practice. Please contact Gary Chandler to join our coalition for reform firstname.lastname@example.org. Stop prion disease.