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LEICESTER, U.K.—It was just last year that researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester identified a major pathway leading to brain cell death in mice; now they have used an orally administered compound to block the pathway and prevent neurodegeneration in those mice.
The team had previously discovered—and published in Nature their findings—that the accumulation of misfolded proteins in the brains of mice with prion disease “over- activates” a natural defense mechanism in cells, which switches off the production of new proteins. This mechanism would normally switch back on again, but in these mice the continued build-up of misshapen protein keeps the switch turned off.
This is the trigger point leading to brain cell death, they say, as the key proteins essential for nerve cell survival stop being made.
Originally, the team injected a protein that blocked the “off switch” of the pathway into a small region of the brain, and by so doing were able to restore protein production and halt neurodegeneration. They found that the brain cells were protected and protein levels and synaptic transmission were restored, allowing the mice to live longer. This led the scientists to predict that compounds able to block this pathway would also protect brain cells.
In the new study, published in October in Science Translational Medicine, the researchers gave an oral drug-like compound against the pathway to prion-infected mice, hoping to block the off switch in the same way. The compound, which had originally been developed by GlaxoSmithKline for a different purpose, was able to enter the brain from the bloodstream and halt the disease throughout the entire brain, they reported.
Speaking of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis and their therapeutic approach, they wrote, “We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.”
However, the compound they used, despite protecting the brain, also produced weight loss in the mice and produced mild diabetes because of damage to the pancreas. The team wasn’t able to study that group of mice at greater length because, despite brain protection, they lost 20 percent of their body weight. Under Home Office regulations, that meant they had to be killed.
Prof. Giovanna Mallucci, who led the team, said, “We’re still a long way from a usable drug for humans—this compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility.”
“Misshapen proteins in prion diseases and other human neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, also over- activate this fundamental pathway controlling protein synthesis in the brains of patients,” added Prof. Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board. “Despite the toxicity of the compound used, this study indicates that, in mice at least, we now have proof-of- principle of a therapeutic pathway that can be targeted. This might eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.”
The recent Science Translational Medicine paper is titled “An oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice” and appeared Oct. 9.