Therapeutic perspectives for prion diseases in humans and animals DOI Creative Commons
Rebeca Benavente, Rodrigo Morales

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(12), P. e1012676 - e1012676

Published: Dec. 10, 2024

Prion diseases are a group of fatal neurodegenerative disorders affecting several mammals including humans, cattle, cervids, sheep, goats, and others [1-3].These driven by the misfolding cellular prion protein (PrP C ) into β-sheet rich structures.The diseaseassociated prion, termed PrP Sc , is prone to aggregation as well neurotoxic [4][5][6].Prion can be associated with mutations in gene (PRNP), induced exposure prion-contaminated materials, or arise sporadically [3,7].A relevant area research field drug discovery.Despite many efforts spanning decades, still have no significant modifying treatments cures [1,2,[7][8][9][10].Several factors affect development effective anti-prion different conformations that particles acquire (also known strains [7,11]), limited number available studied cell-culture models [1], rare incidence human limit patient recruitment, elusive understanding pathogenesis, among [7,12].Moreover, lack sensitive detection methods identify disease its early stages [13] makes it hard treat individuals before onset symptoms when brain damage already extensive likely irreversible [3].This article focuses on approaches used develop therapies targeting pathological pathways.We also discuss been employed evaluate new therapies.Finally, we some therapeutic strategies tested humans animals, future perspectives for against diseases.

Language: Английский

In vivo base editing extends lifespan of a humanized mouse model of prion disease DOI Creative Commons
Meirui An, Jessie R. Davis, Jonathan M. Levy

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract Prion disease is a fatal neurodegenerative caused by the misfolding of prion protein (PrP) encoded PRNP gene. While there currently no cure for disease, depleting PrP in brain an established strategy to prevent or stall templated PrP. Here we developed vivo cytosine and adenine base strategies delivered adeno-associated viruses permanently modify locus achieve knockdown mouse brain. Systemic injection dual-adeno-associated virus PHP.eB encoding BE3.9max single guide RNA installing R37X resulted 37% average installation desired edit, 50% reduction 52% extension lifespan transgenic human mice inoculated with pathogenic isolates representing most common sporadic genetic subtypes disease. We further engineered editing systems improved potency reduced editor expression nontargeting tissues, resulting 63% from 6.7-fold lower viral dose, detected off-target anticipated clinical significance observed either cells tissues. These findings support potential as one-time treatment

Language: Английский

Citations

2
CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model DOI Creative Commons
Lei Wan, Ping Zhong, Pei Li

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 206, P. 106826 - 106826

Published: Feb. 1, 2025

Language: Английский

Citations

1
Precision epigenetic editing: Technological advances, enduring challenges, and therapeutic applications DOI

Goldie V. Roth,

Isabella R. Gengaro, Lei S. Qi

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(8), P. 1422 - 1446

Published: Aug. 1, 2024

Language: Английский

Citations

6
An engineered adeno-associated virus mediates efficient blood-brain barrier penetration with enhanced neurotropism and reduced hepatotropism DOI Creative Commons
Nengsong Luo,

Kunzhang Lin,

Yuxiang Cai

et al.

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 379, P. 303 - 315

Published: Jan. 13, 2025

The blood-brain barrier (BBB) is a formidable that restricts the entry of substances into brain, complicating study brain function and treatment neurological conditions. Traditional methods delivering genes from periphery to central nervous system (CNS) using adeno-associated viruses (AAVs) often require high doses, which can trigger immune responses hepatotoxicity. Here, we developed new AAV variant named AAVhu.32-PLUS based on rational strategy. Following intravenous injection, cross BBB exhibits higher efficiency specificity in transducing neurons significantly reduced hepatotropism compared extensively used AAV-PHP.eB. Furthermore, through vitro cell experiments, identified may rely LY6A receptor for crossing BBB. Finally, our research indicates AAVhu.32-PLUS, while having lower transduction astrocytes AAV-PHP.eB, still capable efficiently glioblastoma after injection. These properties make promising tool neuroscience targeted therapies disease.

Language: Английский

Citations

0
Identification of Chlorogenic Acids from Moringa oleifera Leaves as Modulators of Prion Aggregation Using Affinity Selection-Mass Spectrometry DOI Creative Commons
Magali Silva de Amorim,

Manuela Amaral-do-Nascimento,

Vanessa Gisele Pasqualotto Severino

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Prion diseases are fatal neurodegenerative disorders caused by the misfolding and aggregation of cellular prion protein (PrPC) into its pathogenic form (PrPSc), leading to progressive neurodegeneration. Currently, no effective treatments available, highlighting need for novel therapeutic strategies. In this study, we explored potential Moringa oleifera extracts as a source bioactive compounds that could modulate aggregation. A hydroethanolic extract from M. leaves was analyzed using PrP inhibition profiling via real-time quaking-induced conversion (RT-QuIC) assays, in combination with affinity selection-mass spectrometry (AS-MS). This approach identified chlorogenic neochlorogenic acids potent inhibitors These exhibited significant antiprion activity, IC50 values 64.41 ± 12.12 35.34 7.09 μM, respectively. addition inhibiting PrPC PrPSc, both disaggregate preformed PrPSc fibrils vitro. AS-MS proved be valuable tool isolating modulators directly crude natural product extracts, avoiding expensive time-consuming fractionation purification processes. Identifying highlights products combating other amyloidogenic disorders. Our findings suggest these serve promising lead developing diseases. Further vivo studies pharmacokinetic optimization warranted explore their full potential.

Language: Английский

Citations

0
Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease DOI Creative Commons
Andrew R. Castle, David Westaway

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(1)

Published: Jan. 1, 2025

ABSTRACT Highly abundant in neurons, the cellular prion protein (PrP C ) is an obligatory precursor to disease‐associated misfolded isoform denoted PrP Sc that accumulates rare neurodegenerative disorders referred either as transmissible spongiform encephalopathies (TSEs) or diseases. The ability of serve a substrate for this template‐mediated conversion process depends on several criteria but importantly includes presence absence certain endoproteolytic events performed at cell surface acidic endolysosomal compartments. major affecting are α‐ and β‐cleavages, review we outline sites within which cleavages occur, mechanisms potentially responsible their relevance pathology. Although association α‐cleavage with neuroprotection well‐supported, identify open questions regarding importance β‐cleavage TSEs suggest experimental approaches could provide clarification. We also combine findings from vitro cleavage assays mass spectrometry‐based studies fragments brain present updated view β‐cleavages may represent two distinct clusters proteolytic occur multiple neighbouring rather than single positions. Furthermore, highlight candidate best supported by literature; currently, despite proteases identified capable processing vitro, cell‐based models some cases, vivo, none have been shown conclusively cleave brain. Addressing knowledge gap will be crucial developing therapeutic interventions drive endoproteolysis neuroprotective direction. Finally, end briefly addressing other events, specifically ectodomain shedding, γ‐cleavage, generation atypical pathological familial disorder Gerstmann–Sträussler–Scheinker syndrome possibility additional form close N‐terminus. image

Language: Английский

Citations

0
Characterization of Rationally Designed CRISPR/Cas9-Based DNA Methyltransferases with Distinct Methyltransferase and Gene Silencing Activities in Human Cell Lines and Primary Human T Cells DOI
Rosa Selenia Guerra-Resendez,

Samantha LeGoff Lydon,

J. Alex

et al.

ACS Synthetic Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Nuclease-deactivated Cas (dCas) proteins can be used to recruit epigenetic effectors, and this class of editing technologies has revolutionized the ability synthetically control mammalian epigenome transcriptome. DNA methylation is one most important well-characterized modifications in mammals, while many different forms dCas-based methyltransferases (dCas-DNMTs) have been developed for programmable methylation, these tools are frequently poorly tolerated and/or lowly expressed cell types. Further, use dCas-DNMTs largely restricted lines, which limits mechanistic insights karyotypically normal contexts hampers translational utility longer term. Here, we extend previous into rational design catalytic core DNMT3A methyltransferase test three dCas9-DNMT3A/3L variants across human lines primary donor-derived T cells. We find that mutations within stabilize expression fusion Jurkat cells without sacrificing or gene-silencing performance. also show rationally engineered alter profiles at loci targeted with Finally, leverage transcriptionally repressive effects functionally link a key immunomodulatory transcription factor cytokine secretion Overall, our work expands synthetic biology toolkit provides roadmap DNMTs

Language: Английский

Citations

0
Investigating the In Vivo Effects of Anti-Prion Protein Nanobodies on Prion Disease with AAV Vector DOI Creative Commons
Jingjing Zhang, Mengfei Wang, Dan Wang

et al.

Pathogens, Journal Year: 2025, Volume and Issue: 14(2), P. 131 - 131

Published: Feb. 2, 2025

Prion diseases are fatal neurodegenerative disorders affecting humans and animals, the central pathogenic event is conversion of normal prion protein (PrPC) into PrPSc isoform. Previous studies have identified nanobodies that specifically recognize PrPC inhibit to in vitro. In this study, we investigated potential for vivo expression anti-PrPC evaluated their impact on disease. The coding sequences three were packaged recombinant adeno-associated virus (rAAV) administered via intracerebroventricular (ICV) injection newborn mice. We found these remained robust over 180 days, with no observed detrimental effects. To assess therapeutic potential, performed ICV injections nanobody-expressing rAAVs mice, followed by intracerebral inoculation at 5–6 weeks age. One nanobody exhibited a small yet statistically significant effect, extending survival time from 176 days 184 days. Analyses diseased brains revealed did not alter pathological changes. Our findings suggest high levels necessary delay disease progression. Further optimization nanobodies, AAV vectors, or delivery methods essential achieve effect.

Language: Английский

Citations

0
Gene therapies for neurogenetic disorders DOI Creative Commons
Orrin Devinsky, Jeff Coller, Rebecca C. Ahrens‐Nicklas

et al.

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
CRISPRoff epigenome editing for programmable gene silencing in human cell lines and primary T cells DOI

Rithu Pattali,

Izaiah J. Ornelas,

Carolyn D. Nguyen

et al.

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2025, Volume and Issue: unknown, P. 517 - 551

Published: Jan. 1, 2025

Language: Английский

Citations

0