Decrease in Skin Prion-Seeding Activity of Prion-Infected Mice Treated with a Compound Against Human and Animal Prions: a First Possible Biomarker for Prion Therapeutics

Abstract

Previous studies have revealed that the infectious scrapie isoform of prion protein (PrPSc) harbored in the skin tissue of patients or animals with prion diseases can be amplified and detected through the serial protein misfolding cyclic amplification (sPMCA) or real-time quaking-induced conversion (RT-QuIC) assays. These findings suggest that skin PrPSc-seeding activity may serve as a biomarker for the diagnosis of prion diseases; however, its utility as a biomarker for prion therapeutics remains largely unknown. Cellulose ethers (CEs, such as TC-5RW), widely used as food and pharmaceutical additives, have recently been shown to prolong the lifespan of prion-infected mice and hamsters. Here we report that in transgenic (Tg) mice expressing hamster cellular prion protein (PrPC) infected with the 263K prion, the prion-seeding activity becomes undetectable in the skin tissues of TC-5RW-treated Tg mice by both sPMCA and RT-QuIC assays, whereas such prion-seeding activity is readily detectable in the skin of untreated mice. Notably, TC-5RW exhibits an inhibitory effect on the in vitro amplification of PrPSc in both skin and brain tissues by sPMCA and RT-QuIC. Moreover, we reveal that TC-5RW is able to directly decrease protease-resistant PrPSc and inhibit the seeding activity of PrPSc from chronic wasting disease and various human prion diseases. Our results suggest that the level of prion-seeding activity in the skin may serve as a useful biomarker for assessing the therapeutic efficacy of compounds in a clinical trial of prion diseases and that TC-5RW may have the potential for the prevention/treatment of human prion diseases.

PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt–Jakob Disease

“…While the RT-QuIC represents one of the major breakthroughs for the antemortem diagnosis of these diseases, it does not provide specific information about the prion strain, thus hampering the possibility to recognize sCJD subtypes and stratify patients when they are alive. This aspect is of fundamental importance since a strain-dependent efficacy of anti-prion compounds has been emerging (Barret et al, 2003;Yung et al, 2004;Cronier et al, 2007;Berry et al, 2013;Ding et al, 2021). In this work, we have evaluated the efficiency of an optimized PMCA to faithfully amplify prion strains across the spectrum of sCJD subtypes using OM samples collected from living patients.…”

Cellulose ether treatment inhibits amyloid beta aggregation, neuroinflammation and cognitive deficits in transgenic mouse model of Alzheimer’s disease

“…It is worthwhile to use innovative and rationale approaches to investigate FDA-approved compounds for repurposing to expedite the development of novel and safe therapeutics to treat AD. Recently, we and other groups tested FDA-approved CEs in prion diseases and found that CEs have therapeutic effects by inhibiting propagation of prions, infectious agents generated upon misfolding of the host's cellular prion protein and prototypic for other misfolded proteins associated with neurodegenerative diseases, and extend the survival of prion-infected mice [30][31][32][33][34][35]. Herein, we tested and validated for the first time FDA-approved CE (HPMC) representative TC-5RW (Type E (Hypromellose 2910 classified by the United States Pharmacopeia)) as a potential, emerging and effective compound to halt and treat familial AD.…”

“…The US Food and Drug Administration (FDA) approved HPMC as a safe pharmaceutical and food additive and reported that quantities up to 670 mg in oral formulations are safe to humans [27][28][29]. However, recently our and other groups' studies showed that CEs have therapeutic effects in neurodegenerative diseases via inhibiting the propagation of prions, infectious agents consisting of a misfolded protein [30][31][32][33][34][35]. Most importantly, subcutaneous (SC) administration of CEs even one year prior to prion infection significantly increased the life span of prion-infected mice [31].…”

The Future of Seed Amplification Assays and Clinical Trials

“…When considering quantification of seeding activity as a pharmacodynamic biomarker, inhibition of the RT-QuIC assay due to direct inhibition of in vitro seeding by anti-aggregation agents complicates interpretation, although estimation of drug concentration in the sample and comparing its inhibitory effect on the RT-QuIC of samples with known seeding activity may aid interpretation (Ding et al, 2021 ). Another complexity of interpretation of RT-QuIC in trials of anti-aggregation agents to consider, particularly in the context of treatment failure, is whether the emergence of a drug-resistant protein strain would be detectable or not, due to potential alteration in RT-QuIC amyloid seeding activity.…”

“…A potential limitation is the patient tolerability of serial lumbar puncture during the clinical trial, although seed amplification assays have been applied to other more accessible analytes. Interestingly in a mouse model of prion disease skin RT-QuIC seeding activity was abolished by treatment with an anti-prion agent that prolonged survival, suggesting a potential role for skin RT-QuIC as a pharmacodynamic biomarker (Ding et al, 2021 ). However, despite the ease of skin biopsy relative to lumbar puncture, CSF remains a more attractive analyte for assessing drug target engagement in the central nervous system owing to its proximity to the brain parenchyma.…”