Current State of Human Gene Therapy: Approved Products and Vectors

Pharmaceuticals, Год журнала: 2023, Номер 16(10), С. 1416 - 1416

Опубликована: Окт. 5, 2023

In the realm of gene therapy, a pivotal moment arrived with Paul Berg’s groundbreaking identification first recombinant DNA in 1972. This achievement set stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and host other ailments, are now being addressed at their root cause—the genetic level. Presently, therapy landscape stands adorned 22 approved vivo ex products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, many more. this comprehensive exploration, we delve into rich assortment 16 drugs, from siRNA, miRNA, CRISPR/Cas9 to aptamers TRAIL/APO2L, as well 46 carriers, AAV, AdV, LNPs, exosomes naked mRNA, sonoporation, magnetofection. The article also discusses advantages disadvantages each product vector type, current challenges faced practical use its potential.

Язык: Английский

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A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

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

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An RNA-targeting CRISPR–Cas13d system alleviates disease-related phenotypes in Huntington’s disease models

Nature Neuroscience, Год журнала: 2022, Номер 26(1), С. 27 - 38

Опубликована: Дек. 12, 2022

Abstract Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Since reduction pathogenic mutant messenger RNA therapeutic, we developed allele-sensitive EX RNA-targeting CRISPR–Cas13d system (Cas13d–CAG that eliminates toxic fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show intrastriatal delivery Cas13d–CAG via an adeno-associated viral vector selectively reduces mRNA protein levels striatum heterozygous zQ175 mice, model HD. This also led to improved motor coordination, attenuated striatal atrophy aggregates. These phenotypic improvements lasted for at least eight months without adverse effects minimal off-target transcriptomic effects. Taken together, demonstrate proof principle as therapeutic approach HD, strategy implications treatment other disorders.

Язык: Английский

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Using human genetics to improve safety assessment of therapeutics

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 22(2), С. 145 - 162

Опубликована: Окт. 19, 2022

Язык: Английский

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Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study

The Lancet Neurology, Год журнала: 2024, Номер 23(3), С. 243 - 255

Опубликована: Янв. 24, 2024

Язык: Английский

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Huntington’s Disease: Latest Frontiers in Therapeutics

Current Neurology and Neuroscience Reports, Год журнала: 2024, Номер 24(8), С. 255 - 264

Опубликована: Июнь 11, 2024

Язык: Английский

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Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington’s Disease Treatment

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(2), С. 783 - 815

Опубликована: Янв. 11, 2024

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by mutation in the huntingtin (HTT) gene, resulting production of mutant protein (mHTT). The accumulation mHTT leads to development toxic aggregates neurons, causing cell dysfunction and, eventually, death. Peptide therapeutics target various aspects HD pathology, including reduction and aggregation inhibition, extended CAG mRNA degradation, modulation dysregulated signaling pathways, such as BDNF/TrkB signaling. In addition, these peptide also detrimental interactions with InsP3R1, CaM, or Caspase-6 proteins mitigate HD. This Perspective provides detailed perspective on anti-HD therapeutic peptides, highlighting their design, structural characteristics, neuroprotective effects, specific mechanisms action. for exhibit promise preclinical models, but further investigation required confirm effectiveness viable strategies, recognizing that no approved therapy currently exists.

Язык: Английский

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Chondrocyte‐Targeted Delivery System of Sortase A‐Engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy

Advanced Healthcare Materials, Год журнала: 2024, Номер 13(16)

Опубликована: Март 28, 2024

Abstract Targeted drug delivery and the reduction of off‐target effects are crucial for promising clinical application nucleic acid drugs. To address this challenge, a new approach treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase‐13 (ASO‐MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) ligated with chondrocyte affinity peptide (CAP) using Sortase A subsequently incubated cholesterol‐modified ASO‐MMP13 construct chondrocyte‐targeted exo (CAP‐exoASO). Compared exos without CAP (ExoASO), CAP‐exoASOs attenuate IL‐1β‐induced damage prolong retention time in joint distribution major organs following intra‐articular injection. Notably, decrease MMP13 expression ( P < 0.001) upregulate COL2A1 = 0.006), resulting reorganization cartilage alleviation progression OA model. Furthermore, Osteoarthritis Research Society International (OARSI) score articular tissues treated CAP‐exoASO comparable healthy rats 0.148). mechanistic study demonstrates may reduce inflammation by suppressing IL‐17 TNF signaling pathways. Based on targeted effect, successfully accomplish repair have considerable potential development as therapeutic modality satisfactory therapy.

Язык: Английский

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Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases

Pharmaceutics, Год журнала: 2022, Номер 14(8), С. 1708 - 1708

Опубликована: Авг. 16, 2022

Antisense oligonucleotides (ASOs) are single-stranded nucleic acid strings that can be used to selectively modify protein synthesis by binding complementary (pre-)mRNA sequences. By specific arrangements of DNA and RNA into a chain acids additional modifications the backbone, sugar, base, specificity functionality designed ASOs adjusted. Thereby cellular uptake, toxicity, nuclease resistance, as well affinity its target (pre-)mRNA, modified. Several neurodegenerative diseases caused autosomal dominant toxic gain-of-function mutations, which lead products driving disease progression. targeting such mutations—or even more comprehensively, associated variants, single nucleotide polymorphisms (SNPs)—promise selective degradation mutant while sparing wild type allele. this approach, expression from strand is preserved, side effects an unselective knockdown both alleles prevented. This makes allele-specific strategies focus for future personalized therapies. Here, we provide overview current develop personalized, ASO therapies treatment diseases, Huntington’s (HD) spinocerebellar ataxia 3 (SCA3/MJD).

Язык: Английский

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Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 3, 2022

Abstract Small interfering RNAs are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing gene expression in vivo. We recently demonstrated that siRNA chemical architectures can be optimized to provide efficient delivery the CNS, enabling development CNS-targeted therapeutics. Many genetically-defined neurodegenerative disorders dominant, favoring selective mutant allele. In some cases, successfully targeting allele requires single nucleotide polymorphism (SNP) heterozygosities. Here, we use Huntington’s disease (HD) as model. The compound exhibits huntingtin protein patient-derived cells throughout HD mouse brain, demonstrating SNP-based allele-specific RNAi vivo CNS. Targeting disease-causing using RNAi-based therapies could helpful range dominant CNS where maintaining wild-type is essential.

Язык: Английский

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