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Full-Text Articles in Medicine and Health Sciences
Prion Protein Lowering Is A Disease-Modifying Therapy Across Prion Disease Stages, Strains And Endpoints, Eric Vallabh Minikel, Hien T. Zhao, Jason Le, Jill O'Moore, Rose Pitstick, Samantha Graffam, George A. Carlson, Michael P. Kavanaugh
Prion Protein Lowering Is A Disease-Modifying Therapy Across Prion Disease Stages, Strains And Endpoints, Eric Vallabh Minikel, Hien T. Zhao, Jason Le, Jill O'Moore, Rose Pitstick, Samantha Graffam, George A. Carlson, Michael P. Kavanaugh
Biomedical and Pharmaceutical Sciences Faculty Publications
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine 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. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. 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. Remarkably, 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.
Reduced Expression Of The Pp2a Methylesterase, Pme-1, Or The Pp2a Methyltransferase, Lcmt-1, Alters Sensitivity To Beta-Amyloid-Induced Cognitive And Electrophysiological Impairments In Mice, Agnieszka Staniszewski, Hong Zhang, Kesava Asam, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls
Reduced Expression Of The Pp2a Methylesterase, Pme-1, Or The Pp2a Methyltransferase, Lcmt-1, Alters Sensitivity To Beta-Amyloid-Induced Cognitive And Electrophysiological Impairments In Mice, Agnieszka Staniszewski, Hong Zhang, Kesava Asam, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls
Biomedical and Pharmaceutical Sciences Faculty Publications
Beta-amyloid (Ab) is thought to play a critical role in Alzheimer’s disease (AD), and application of soluble oligomeric forms of Ab produces AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic overexpression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Ab-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely applied synthetic Ab oligomers in male and female mice heterozygous for either a PME-1 KO or …