Prion disease is a rapidly fatal and currently untreatable neurodegenerative disease. Although rare, with roughly 300 cases reported each year in the United States, it typically causes rapid neurodegeneration. The more common forms of prion disease that affect humans are Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, also known as mad cow disease.

Prion disease is caused by the post-translational disruption of the structure of a human prion protein (PrP) producing toxic clumps in the brain. Due to its central role in disease pathophysiology, lowering PrP expression in the brain is a genetically validated, promising therapeutic approach in prion disease.

A new study suggests a possible effective treatment strategy for patients suffering from prion disease. The researchers reported the results of preclinical studies of an antisense therapy against 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 intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms.

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 timepoint, and examining symptomatic, survival, and biomarker readouts.”

Vallabh’s team, in addition to teams at 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 recapitulated 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 neuroinflammation 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 timepoints. 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.

Remarkably, the authors wrote, “Even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of 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,” said Vallabh, “these data give 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.”

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