Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope

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

Опубликована: Фев. 17, 2024

Abstract Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer to further increase the activity scope of We first use domain insertion position deaminase nearer displaced DNA strand in target-bound complex. These domain-inlaid variants exhibit shifted windows increased comparison N-terminally fused Nme2-ABE. next expand by swapping PAM-interacting that SmuCas9, which had previously defined recognizing single-cytidine PAM. then these enhancements introduce therapeutically relevant edits variety cell types. Finally, validate Nme2-ABEs for single-AAV delivery vivo.

Язык: Английский

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Preparing for Patient-Customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases

Genes, Год журнала: 2024, Номер 15(7), С. 821 - 821

Опубликована: Июнь 21, 2024

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability build effective treatments. Recently, a novel type therapy called antisense has shown immense potential for the treatment diseases, particularly through single-patient N-of-1 trials. Several been developed recently including landmark study milasen. In response success therapy, Food Drug Administration (FDA) unique guidelines specifically development diseases. This policy change establishes strong foundation future addresses some major limitations previously hindered

Язык: Английский

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Neuronal Ceroid Lipofuscinosis—Concepts, Classification, and Avenues for Therapy

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(2)

Опубликована: Фев. 1, 2025

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation lipofuscin. Thirteen subtypes NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory or enzymes. Clinically, manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, premature death. The pathological complexity has hindered the development effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene stem cell demonstrated limited efficacy. However, emerging evidence suggests significant relationship between microglial cells, highlighting potential novel therapies. This review comprehensively examines pathogenic subtypes, elucidating their roles, presentations, corresponding mouse models. Especially, we thoroughly discuss advances study therapeutics, which crucially calls for early diagnosis more than ever.

Язык: Английский

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Preparing for patient-customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases

Опубликована: Май 29, 2024

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability build effective treatments. Recently, a novel type therapy called antisense has shown immense potential for the treatment diseases, particularly through single-patient N-of-1 trials. Several been developed recently including landmark study milasen. In response success therapy, Food Drug Administration (FDA) unique guidelines specifically development diseases. This policy change establishes strong foundation future development, addresses some major limitations previously hindered

Язык: Английский

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Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

Genes, Год журнала: 2024, Номер 15(3), С. 290 - 290

Опубликована: Фев. 25, 2024

Rare diseases, or orphan are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), cluster rare metabolic characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and lower risk failure. We present comprehensive analysis drugs, their potential, clinical implications context LSDs, highlighting necessity mutation-specific approaches. Our review systematically explores landscape drug means enhance LSDs therapies. The findings advocate strategic accentuating its role expediting discovery effective treatments. conclude that represents viable pathway accelerating emphasizing need careful evaluation efficacy toxicity disease-specific contexts.

Язык: Английский

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Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Batten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in

Язык: Английский

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Splice-switching antisense oligonucleotides for pediatric neurological disorders

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Июль 25, 2024

Pediatric neurological disorders are frequently devastating and present unmet needs for effective medicine. The successful treatment of spinal muscular atrophy with splice-switching antisense oligonucleotides (SSO) indicates a feasible path to targeting by redirecting pre-mRNA splicing. One direct outcome is the development SSOs treat haploinsufficient naturally occurring non-productive splice isoforms. personalized SSO further inspired therapeutic exploration rare diseases. This review will discuss recent advances that utilize pediatric disorders.

Язык: Английский

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Antisense oligonucleotides in rare neurogenetic disorders

Journal of Genetic Medicine, Год журнала: 2024, Номер 21(2), С. 41 - 50

Опубликована: Дек. 31, 2024

Rapid advancements in genetic testing have significantly improved the diagnosis of rare diseases.However, development targeted therapies has progressed more slowly, leaving most conditions without effective treatment.Because 80% disorders involve nervous system, early intervention is crucial, particularly pediatric patients with progressive conditions.Antisense oligonucleotides (ASOs) emerged as promising therapeutics that offer precise modulation gene expression through RNA targeting, requiring viral delivery systems.These been successful modulating disease trajectories, thereby demonstrating potential precision medicine.Recent innovations ASO chemical modifications and strategies enhanced their safety, stability, tissue specificity, broadening applicability complex neurogenetic disorders.This review explores mechanisms, clinical applications, future ASOs, emphasizes growing role medicine.As diagnostics evolve alongside therapeutics, ASOs are expected to become key pillars for addressing unmet medical needs transforming management previously untreatable disorders.

Язык: Английский

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Systematic deletion of symmetrical CFTR exons reveals new therapeutic targets for exon skipping antisense oligonucleotides

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract There is a major need for therapeutics that treat diseases caused by pathogenic gene variants disrupt protein open-reading frames. Splice-switching antisense oligonucleotides (ASOs) offer potential solution inducing the skipping of exons containing these variants, removing them from mRNA and correcting frame. Cystic fibrosis (CF), disruption CF transmembrane regulator ( CFTR ) gene, one such disease has many chain-terminating which are untreatable with standard protein-targeted modulator therapies. Using as model, we demonstrate utility ASOs in engineering isoforms through exon to rescue function disrupted truncating variants. We functionally screened all generated deletion symmetrical exons, can be skipped without disrupting identified removed produce remain responsive modulators. induce show they recover airway cells derived individuals terminating This study demonstrates systematic functional analysis in-frame exon-deleted identify targets ASO-based splice-switching therapies, concept broadly applied any multi-exon protein-coding gene.

Язык: Английский

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CLN3 transcript complexity revealed by long-read RNA sequencing analysis

BMC Medical Genomics, Год журнала: 2024, Номер 17(1)

Опубликована: Окт. 4, 2024

Язык: Английский

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