Drug Targets Toxic Proteins In Brain
Neurodegenerative disease is surging around the world. It’s the fastest-growing cause of death and it will soon be the leading cause of death.
Alzheimer’s disease alone is taking the lives of 50-100 million people around the world now. Millions will die of the disease this year, while many millions more will be diagnosed, misdiagnosed and undiagnosed. The epidemic is more severe in some countries than others. Despite millions of deaths annually, experts suggest that the prevalence of Alzheimer’s disease will quadruple by 2050, if not sooner. Unfortunately, there is a growing stack of evidence that Alzheimer’s disease, Parkinson’s disease and other brain diseases are transmissible. Deadly proteins are responsible for the pandemic.
Prions (PREE-ons) are a deadly and unstoppable form of protein that migrates, mutates, multiplies and kills with unparalleled efficiency. Prions cause fatal neurodegenerative disease in humans and other mammals by converting the cellular version of prion protein into a toxic form that erodes the brain and body.
Prion disease is described as a wasting disease that causes a loss of body mass and brain mass.
Dr. Stanley Prusiner, an American neuroscientist from the University of California at San Francisco, earned a Nobel Prize in 1997 for discovering and characterizing prions and prion disease. President Obama awarded Prusiner the National Medal of Science in 2010 to recognize the importance of his research. Important reforms to policies to protect public health, however, have been elusive.
Prion disease is a rapidly fatal and currently untreatable neurodegenerative disease that impacts mammals around the globe. The disease is always fatal and it is highly transmissible. The epidemic is rapidly becoming the fastest-growing cause of death in the world. Contrary to popular belief, it’s killing people of all ages, not just the elderly.
The most common form of prion disease that affects humans is Creutzfeldt-Jakob disease (CJD). However, Nobel Laureate Stanley Prusiner identified Alzheimer’s disease and Parkinson’s disease as forms of prion disease. Mad cow disease (livestock) and chronic wasting disease (wildlife) also are forms of prion disease that threaten humans via food and water contamination.
Prusiner’s most recent study confirms that Alzheimer’s disease is a prion disease, which also is known as transmissible spongiform encephalopathy (TSE).
The operative word is “transmissible.” Alzheimer’s disease is currently defined based on the presence of toxic protein aggregations in the brain known as amyloid plaques and tau tangles, accompanied by cognitive decline and dementia.
So far, attempts to treat the disease by clearing these proteins from the brain have been unsuccessful. However, a new study offers hope for an effective treatment strategy for prion disease. Senior author Sonia Vallabh, PhD, associate scientist at the Broad Institute, had previously shown that antisense oligonucleotides (ASOs) reduced levels of prion protein, extended the survival of animals infected with misfolded prions, and delayed disease onset in prion-infected mice in both prophylactic and delayed dosing situations.
While these initial data were promising, many critical questions remained before therapeutic development could be possible. In this current work, the group examined the efficacy of this therapeutic approach “across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timing, and examining symptomatic, survival, and biomarker readouts.”
Vallabh’s team, in collaboration Ionis Pharmaceuticals and the McLaughlin Research Institute, reported the results of preclinical studies of an antisense therapy against prion disease.
The research is published in the article titled, “Prion Protein Lowering is a Disease-modifying Therapy Across Prion Strains, Stages, and Endpoints,” in Nucleic Acids Research.
In this work, the authors have abandoned their previous findings with additional PrP-targeting ASOs, and demonstrated therapeutic benefit against four additional prion strains, laying the basis for full scale clinical development. This research showed that, across multiple treatment paradigms, reducing levels of prion protein in prion-infected lab animals significantly extended their survival.
Specifically, the authors noted the results demonstrated that <25% PrP suppression “is sufficient to extend survival and delay symptoms in a prophylactic paradigm. A rise in both neuron inflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout.”
The researchers showed that reducing levels of prion protein can triple the survival of prion-infected animals. Even reducing prion protein levels by a small amount, which should be easier to achieve clinically, resulted in significant survival benefits.
Reduction of prion protein is effective across prion strains and across a battery of different treatment timeframes. The researchers showed that reducing prion protein is effective before any symptoms are seen. They also demonstrated, for the first time, that a single dose of a prion protein-lowering treatment can reverse markers of disease even after toxic clumps have formed in the brain.
Even after emergence of symptoms, a single treatment prolongs survival by months in animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.
“While there are still many steps ahead, this research gives us optimism that by aiming straight at the genetic heart of prion disease, genetically targeted drugs designed to lower prion protein levels in the brain may prove effective in the clinic,” said Vallabh.
Prions are such a formidable threat that the U.S. government enacted the Bioterrorism Preparedness and Response Act of 2002, which included a provision to halt research on prions in all but two laboratories.
The U.S. government initially classified prions as select agents that pose an extreme risk to food, water and health systems. Today, governments don’t regulate prions at all. As such, millions of caregivers are being misinformed, misguided and exposed to an aggressive prion disease. So are friends and family. Unfortunately, Prusiner’s science is being ignored and we are facing a public health disaster because of the negligence and reckless disregard for public health.
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