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, Год журнала: 2025, Номер unknown, С. 1 - 13

Опубликована: Фев. 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.

Язык: Английский

Prediction of on-target and off-target activity of CRISPR–Cas13d guide RNAs using deep learning DOI
Hans‐Hermann Wessels,

Andrew Stirn,

Alejandro Méndez‐Mancilla

и другие.

Nature Biotechnology, Год журнала: 2023, Номер 42(4), С. 628 - 637

Опубликована: Июль 3, 2023

Язык: Английский

Процитировано

56
Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies DOI Open Access
Huichun Tong, Tianqi Yang, Shuying Xu

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3845 - 3845

Опубликована: Март 29, 2024

Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in huntingtin gene (HTT), resulting production mutant protein (mHTT) with a polyglutamine stretch its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates accumulates abnormally neuronal nuclei processes, leading to disruptions multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made developing various therapeutic strategies treat HD. In addition drugs targeting toxicity mHTT, therapy approaches that aim reduce expression HTT hold great promise therapy. This review provides an overview current treatments, discusses different strategies, aims facilitate future advancements field.

Язык: Английский

Процитировано

20
Gene therapy for CNS disorders: modalities, delivery and translational challenges DOI
Jingjing Gao,

Swetharajan Gunasekar,

Ziting Xia

и другие.

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(8), С. 553 - 572

Опубликована: Июнь 19, 2024

Язык: Английский

Процитировано

19
A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD DOI Creative Commons
Tristan X. McCallister, Colin K.W. Lim,

Madhurima Singh

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 8, 2025

Abstract An abnormal expansion of a GGGGCC (G 4 C 2 ) hexanucleotide repeat in the C9ORF72 gene is most common genetic cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven part by gain-of-function mechanisms involving transcribed forms expansion. By utilizing Cas13 variant with reduced collateral effects, we develop here high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to brain transgenic rodent model, this Cas13-based platform curbed expression G repeat-containing RNA without affecting normal levels, which turn decreased formation foci, production dipeptide protein, reversed transcriptional deficits. This possessed improved transcriptome-wide specificity compared its native form mediated targeting motor neuron-like cells derived from patient ALS. These results lay foundation implementation CRISPR technologies

Язык: Английский

Процитировано

3
Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo DOI Creative Commons
Liam Kempthorne, Deniz Vaizoglu, Alexander J. Cammack

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 8, 2025

Abstract The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G 4 C 2 repeat expansion in C9orf72 . repeats undergo bidirectional transcription to produce sense antisense RNA species, which are translated into dipeptide proteins (DPRs). As toxicity has been associated with both repeat-derived DPRs, targeting strands may provide the effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing multiple species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed transcripts DPRs HEK cells. In patient-derived iPSC-neuron lines, CRISPR-CasRx endogenous RNAs protects against glutamate-induced excitotoxicity. AAV delivery two distinct mouse models significantly reduced repeat-containing transcripts. This highlights potential RNA-targeting CRISPR as therapeutics for ALS/FTD.

Язык: Английский

Процитировано

2
Multiplexed inhibition of immunosuppressive genes with Cas13d for combinatorial cancer immunotherapy DOI
Feifei Zhang, Ryan D. Chow, Emily He

и другие.

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

2
Precise RNA targeting with CRISPR–Cas13d DOI
Sydney K. Hart, Simon Müller, Hans‐Hermann Wessels

и другие.

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Язык: Английский

Процитировано

2
An Update on the Application of CRISPR Technology in Clinical Practice DOI Open Access
Firouzeh Morshedzadeh, Mahmoud Ghanei,

Malihe Lotfi

и другие.

Molecular Biotechnology, Год журнала: 2023, Номер 66(2), С. 179 - 197

Опубликована: Июнь 3, 2023

Язык: Английский

Процитировано

23
Massively parallel profiling of RNA-targeting CRISPR-Cas13d DOI Creative Commons
Hung‐Che Kuo,

Joshua Prupes,

Chia‐Wei Chou

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 12, 2024

Abstract CRISPR-Cas13d cleaves RNA and is used in vivo for diagnostics. However, a systematic understanding of its binding cleavage specificity lacking. Here, we describe an Chip-Hybridized Association-Mapping Platform (RNA-CHAMP) measuring the affinity > 10,000 RNAs containing structural perturbations other alterations relative to CRISPR (crRNA). Deep profiling Cas13d reveals that it does not require protospacer flanking sequence but exquisitely sensitive secondary structure within target RNA. penalized by mismatches distal crRNA-target region, while proximal region inhibit nuclease activity. A biophysical model built from these data recognition initiates end Using this model, design crRNAs can differentiate between SARS-CoV-2 variants modulating activation. This work describes key determinants targeting type VI enzyme.

Язык: Английский

Процитировано

10
Targeted Macrophage CRISPR‐Cas13 mRNA Editing in Immunotherapy for Tendon Injury DOI
Shuo Wang, Yao Xiao, Jian Tian

и другие.

Advanced Materials, Год журнала: 2024, Номер 36(19)

Опубликована: Фев. 2, 2024

Abstract CRISPR‐Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during acute stages of tendon injury. In this investigation, macrophage‐targeting cationic polymers are systematically screened to facilitate entry Cas13 ribonucleic‐protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)‐producing recognized as a profibrotic subtype that emerges stage. By employing ROS‐responsive release mechanisms tailored macrophage‐targeted RNP systems, overactivation is curbed face an immune microenvironment. Upon encapsulating composite membrane around injury site, effectively curtails emergence injury‐induced SPP1‐producing phase, leading diminished fibroblast activation mitigated peritendinous adhesion. Consequently, study furnishes strategy phase triggered ROS injury, along with pioneering carrier proficient delivering efficiently.

Язык: Английский

Процитировано

10