Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy DOI Creative Commons

Agamjot Sangotra,

Andrew P. Lieberman

Expert Opinion on Therapeutic Targets, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: Feb. 7, 2025

Spinal and Bulbar Muscular Atrophy (SBMA) is a slowly progressive, X-linked, sex-limited degenerative disorder affecting lower motor neurons skeletal muscle which lacks disease-modifying therapies. This disease caused by CAG/polyglutamine (polyQ) tract expansion in the androgen receptor (AR) gene, its pathogenesis driven toxic gain-of-function mechanisms. Affected men develop proximal limb bulbar weakness along with signs of partial insensitivity. Toxicity polyQ AR mediated protein misfolding nuclear translocation that follow ligand binding, resulting disruption downstream homeostatic review highlights what known about how this has been leveraged to test potential therapeutic approaches. The focus on strategies alleviate toxicity SBMA, including those alter function, diminish expression encoding or promote clearance misfolded, mutant protein. We discuss emerging mitigate toxicity, gene editing, RNA targeted therapies, efforts harness proteostatic These promising approaches are discussed context challenges for drug discovery faced when attempting treat rare progressive neurodegenerative disorder.

Language: Английский

Cytosolic CRISPR RNAs for efficient application of RNA-targeting CRISPR-Cas systems DOI Creative Commons

Ezra C.K. Cheng,

Jodie Lam,

S. Chul Kwon

et al.

EMBO Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Abstract Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technologies have evolved rapidly over the past decade with continuous discovery of new Cas systems. In particular, RNA-targeting CRISPR-Cas13 proteins are promising single-effector systems to regulate target mRNAs without altering genomic DNA, yet current Cas13 restrained by suboptimal efficiencies. Here, we show that U1 promoter-driven CRISPR RNAs (crRNAs) increase efficiency various applications, including RNA knockdown and editing, modifying effector. We confirm U1-driven crRNAs exported into cytoplasm, while conventional U6 mostly confined nucleus. Furthermore, reveal end positions expressed promoter consistent regardless guide sequences lengths. also demonstrate crRNAs, but not U6-driven can efficiently repress translation genes in combination catalytically inactive proteins. Finally, counteract inhibitory effect miRNAs. Our simple effective engineering enables unprecedented cytosolic applications.

Language: Английский

Citations

0
Treatment of autosomal dominant retinitis pigmentosa caused by RHO-P23H mutation with high-fidelity Cas13X in mice DOI Creative Commons
Zixiang Yan, Yuqin Yao, Luyao Li

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 33, P. 750 - 761

Published: Aug. 8, 2023

Mutations in Rhodopsin (RHO) gene commonly cause autosomal dominant retinitis pigmentosa (adRP) without effective therapeutic treatment so far. Compared with genomic DNA-targeting CRISPR-Cas9 system, Cas13 edits RNA for applications, avoiding the risk of causing permanent changes genome. In particular, a compact and high-fidelity Cas13X (hfCas13X) recently has been developed to degrade targeted minimal collateral effects could also be packaged single adeno-associated virus efficient vivo delivery. this study, we engineered single-guide hfCas13X specifically knock down human mutant transcripts RHO-P23H effect on wild-type transcripts. Moreover, alleviated adRP progression both overexpression-induced humanized hRHOP23H/WT mouse models. Our study indicates potential treating caused by RHO mutations other genetic diseases.

Language: Английский

Citations

11
Advances in Gene and Cellular Therapeutic Approaches for Huntington’s Disease DOI Creative Commons
Xuejiao Piao, Dan Li, Hui Liu

et al.

Protein & Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the abnormal expansion of CAG trinucleotide repeats in Huntingtin gene (HTT) located on chromosome 4. It transmitted autosomal dominant manner and characterized motor dysfunction, cognitive decline, emotional disturbances. To date, there are no curative treatments for HD have been developed; current therapeutic approaches focus symptom relief comprehensive care through coordinated pharmacological nonpharmacological methods to manage diverse phenotypes disease. International clinical guidelines treatment continually being revised effort enhance within a multidisciplinary framework. Additionally, innovative cell therapy strategies actively researched developed address complexities improve outcomes. This review endeavours elucidate emerging HD, offering detailed insight into looking forward future paradigms. Considering complexity underlying mechanisms driving synergistic strategy that integrates various factors—such as distinct types, epigenetic patterns, genetic components, cerebral microenvironment—may significantly In future, we eagerly anticipate ongoing innovations interdisciplinary research will bring profound advancements refinements HD.

Language: Английский

Citations

4
Advances in Huntington’s Disease Biomarkers: A 10-Year Bibliometric Analysis and a Comprehensive Review DOI Creative Commons
Sarah Aqel, Jamil Ahmad,

Iman Saleh

et al.

Biology, Journal Year: 2025, Volume and Issue: 14(2), P. 129 - 129

Published: Jan. 26, 2025

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global of death within two decades. Huntington’s disease (HD) is rare, ND caused by an autosomal-dominant mutation in huntingtin (HTT) gene, severe brain resulting debilitating motor, cognitive, psychiatric symptoms. Given complex pathology HD, biomarkers essential for performing early diagnosis, monitoring progression, evaluating treatment efficacy. However, identification consistent HD challenging due prolonged premanifest stage, HD’s heterogeneous presentation, its multiple underlying biological pathways. This study involves 10-year bibliometric analysis biomarker research, revealing key research trends gaps. The also features comprehensive literature review emerging biomarkers, concluding need better stratification patients well-designed longitudinal studies validate biomarkers. Promising candidate wet biomarkers— including neurofilament light chain protein (NfL), microRNAs, mutant HTT protein, specific metabolic inflammatory markers— discussed, emphasis on their potential utility stage. Additionally, reflecting structural deficits motor or behavioral impairments, such as neurophysiological (e.g., tapping, speech, EEG, event-related potentials) imaging MRI, PET, diffusion tensor imaging) evaluated. findings underscore that discovery validation reliable urgently require improved patient studies. Reliable particularly crucial optimizing clinical management strategies, enabling personalized approaches, advancing trials HD-modifying therapies.

Language: Английский

Citations

0
Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy DOI Creative Commons

Agamjot Sangotra,

Andrew P. Lieberman

Expert Opinion on Therapeutic Targets, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: Feb. 7, 2025

Spinal and Bulbar Muscular Atrophy (SBMA) is a slowly progressive, X-linked, sex-limited degenerative disorder affecting lower motor neurons skeletal muscle which lacks disease-modifying therapies. This disease caused by CAG/polyglutamine (polyQ) tract expansion in the androgen receptor (AR) gene, its pathogenesis driven toxic gain-of-function mechanisms. Affected men develop proximal limb bulbar weakness along with signs of partial insensitivity. Toxicity polyQ AR mediated protein misfolding nuclear translocation that follow ligand binding, resulting disruption downstream homeostatic review highlights what known about how this has been leveraged to test potential therapeutic approaches. The focus on strategies alleviate toxicity SBMA, including those alter function, diminish expression encoding or promote clearance misfolded, mutant protein. We discuss emerging mitigate toxicity, gene editing, RNA targeted therapies, efforts harness proteostatic These promising approaches are discussed context challenges for drug discovery faced when attempting treat rare progressive neurodegenerative disorder.

Language: Английский

Citations

0