Engineered U1 snRNAs to modulate alternatively spliced exons

Hatch, Samuel T.; Yeo, G

doi:10.1016/j.ymeth.2022.06.008

Cited by 9 publications

(3 citation statements)

References 33 publications

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“…The pharmaceutical development program ended in 2019 due to budgetary constraints and the rarity of the patient population. Other feasible therapeutic approaches are small nuclear RNA components [43] or antisense oligonucleotides [44] to treat the splicing defect. Also, gene replacement therapy has been proposed that would entail delivering Type 2 adeno-associated virus (AAV) to express a wild type copy of the ELP1 gene [45] or Type 9 AAV for exon-specific inclusion of ELP1 exon 20 in cells expressing the target pre-mRNA [46].…”

Section: Application To Pediatric Dysautonomias: Familial Dysautonomi...mentioning

confidence: 99%

Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias

Goldstein

2024

JPM

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Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas—the “extended” autonomic system (EAS) and the “homeostat” theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley’s ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon’s theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input–output curves and maintain plateau levels of regulated variables within different bounds of values—“allostasis”. Sustained allostatic processes increase long-term wear-and-tear on effectors and organs—allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias—familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.

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Section: Application To Pediatric Dysautonomias: Familial Dysautonomi...mentioning

confidence: 99%

Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias

Goldstein

2024

JPM

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“…Since U7smOPT technology operates solely through binding and steric hindrance, its main limitation is an inability to induce exon inclusion in a generalizable manner. Engineered U1 snRNAs, which possess all the benefits of U7smOPT, overcome this barrier and have been exploited for robust exon-specific inclusion 83,84 . In addition, the high endogenous expression level of U1 snRNPs (estimated at approximately 1 million copies per cell) suggests that engineered U1 snRNA overexpression may not significantly perturb cellular processes.…”

Section: One Notable Disease Application Formentioning

confidence: 99%

Programmable macromolecule-based RNA-targeting therapies to treat human neurological disorders

Morelli

Yeo

2023

RNA

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Disruptions in RNA processing play critical roles in the pathogenesis of neurological diseases. In this perspective, we discuss recent progress in the development of RNA-targeting therapeutic modalities. We focus on progress, limitations, and opportunities in a new generation of therapies engineered from RNA binding proteins and other endogenous RNA regulatory macromolecules to treat human neurological disorders.

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“…To circumvent this problem, some teams made efforts to produce constructs, which would be able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing the therapeutic antisense sequences [76]. Those constructs are suitable for administration via traditional gene delivery vehicles, thus holding the potential to reduce the frequency of dosing [77].…”

Section: Factors To Consider In the Effectiveness And Use Of Engineer...mentioning

confidence: 99%

Development of Engineered-U1 snRNA Therapies: Current Status

Gonçalves,

Santos,

Coutinho

et al. 2023

IJMS

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Splicing of pre-mRNA is a crucial regulatory stage in the pathway of gene expression. The majority of human genes that encode proteins undergo alternative pre-mRNA splicing and mutations that affect splicing are more prevalent than previously thought. Targeting aberrant RNA(s) may thus provide an opportunity to correct faulty splicing and potentially treat numerous genetic disorders. To that purpose, the use of engineered U1 snRNA (either modified U1 snRNAs or exon-specific U1s—ExSpeU1s) has been applied as a potentially therapeutic strategy to correct splicing mutations, particularly those affecting the 5′ splice-site (5′ss). Here we review and summarize a vast panoply of studies that used either modified U1 snRNAs or ExSpeU1s to mediate gene therapeutic correction of splicing defects underlying a considerable number of genetic diseases. We also focus on the pre-clinical validation of these therapeutic approaches both in vitro and in vivo, and summarize the main obstacles that need to be overcome to allow for their successful translation to clinic practice in the future.

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Engineered U1 snRNAs to modulate alternatively spliced exons

Cited by 9 publications

References 33 publications

Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias

Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias

Programmable macromolecule-based RNA-targeting therapies to treat human neurological disorders

Development of Engineered-U1 snRNA Therapies: Current Status

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