Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T&gt;C

Kaltak, Melita; Bruijn, Petra de; Piccolo, Davide; Lee, Sang-Eun; Dulla, Kalyan; Hoogenboezem, Thomas; Beumer, Wouter; Webster, Andrew R.; Collin, Rob W.J.; Cheetham, Michael E.; Platenburg, Gerard; Swildens, Jim

doi:10.1016/j.omtn.2023.02.020

Cited by 18 publications

(21 citation statements)

References 62 publications

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“…In such cases, it becomes necessary to block regulatory elements to achieve the desired effect of altering splicing outcomes. 85 For instance, the ABCA4 protein plays a pivotal role in eliminating toxic metabolites within the visual cycle. Aberrant splicing, leading to protein loss of function, results in the accumulation of these toxic metabolites, contributing to the development of type 1 Stargardt disease.…”

Section: Splicing Factor-related Diseasesmentioning

confidence: 99%

“…86 Targeting ABCA4 with AONs, especially those directed at the intronic region (ISS), has proven effective in restoring protein expression and mitigating the disease's impact. 85 Another successful example is Nusinersen, an AON designed to target the ISS region of the SMN2 gene, 87 which received FDA approval as a treatment for spinal muscular atrophy. 88 BP-AON (antisense oligonucleotides targeting branch points), through the specific targeting of the spliced BP site upstream of the mutation site in the FKTN gene, effectively reverses the subsequent exon inclusion.…”

Section: Splicing Factor-related Diseasesmentioning

confidence: 99%

“…In certain studies, it has been observed that some splicing mechanisms are inherently intricate, and merely targeting the splice site with AONs may not be sufficient to restore proper splicing. In such cases, it becomes necessary to block regulatory elements to achieve the desired effect of altering splicing outcomes 85 . For instance, the ABCA4 protein plays a pivotal role in eliminating toxic metabolites within the visual cycle.…”

Section: Treatment Of Aberrant Splicingmentioning

confidence: 99%

“…Aberrant splicing, leading to protein loss of function, results in the accumulation of these toxic metabolites, contributing to the development of type 1 Stargardt disease 86 . Targeting ABCA4 with AONs, especially those directed at the intronic region (ISS), has proven effective in restoring protein expression and mitigating the disease's impact 85 . Another successful example is Nusinersen, an AON designed to target the ISS region of the SMN2 gene, 87 which received FDA approval as a treatment for spinal muscular atrophy 88 …”

Section: Treatment Of Aberrant Splicingmentioning

confidence: 99%

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Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Shi,

Tang,

Xiang

2024

Clinical Genetics

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Accurate pre‐mRNA splicing is essential for proper protein translation; however, aberrant splicing is commonly observed in the context of cancer and genetic disorders. Notably, in genetic diseases, these splicing abnormalities often play a pivotal role. Substantial challenges persist in accurately identifying and classifying disease‐induced aberrant splicing, as well as in development of targeted therapeutic strategies. In this review, we examine prevalent forms of aberrant splicing and explore potential therapeutic approaches aimed at addressing these splicing‐related diseases. This summary contributes to a deeper understanding of the complexities about aberrant splicing and provide a foundation for the development of effective therapeutic interventions in the field of genetic disorders and cancer.

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Section: Splicing Factor-related Diseasesmentioning

confidence: 99%

Section: Splicing Factor-related Diseasesmentioning

confidence: 99%

Section: Treatment Of Aberrant Splicingmentioning

confidence: 99%

Section: Treatment Of Aberrant Splicingmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Shi,

Tang,

Xiang

2024

Clinical Genetics

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“…Notably, antisense oligonucleotides (ASOs) and CRISPR/Cas9 genome editing have been harnessed to effectively interfere with aberrant splicing eventually restoring regular splicing (7,8,9). ASOs function through masking cis -acting sequences on the pre-mRNA which trigger aberrant splicing, thereby preventing their recognition by the spliceosome.…”

Section: Introductionmentioning

confidence: 99%

EDSpliCE, a CRISPR-Cas9 gene editing platform to rescue splicing, effectively corrects inherited retinal dystrophy-associated splicing defects

Angeli,

Shliaga,

Flores-Tufiño

et al. 2024

Preprint

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Background: Correct splicing of transcripts is essential to ensure the production of functional gene products in eukaryotic cells. Missplicing of transcripts has been identified as the underlying molecular mechanisms behind various disease-causing variants in a wide range of inherited genetic conditions. Achieving therapeutic splicing correction is possible through antisense oligonucleotide and CRISPR/Cas9 strategies. However, while antisense oligonucleotides offer effective modulation, they do not enable for permanent correction. On the other hand, current CRISPR/Cas9 approaches often rely on dual-gRNA-inducing deletion of larger pieces of DNA, containing the site(s) responsible for the splicing defect, particularly the elimination of pseudoexons, raising concerns about potential chromosomal instability. Results: The novel gene editing strategy, Enhanced-Deletion Splicing Correction Editing (EDSpliCE), just uses single gRNAs to effectively correct aberrant splicing caused by pseudoexon sequence inclusion into the mature mRNA. By employing Cas9 fused to a human exonuclease (TREX2), EDSpliCE achieves targeted enhanced deletions of sequences involved in pseudoexon recognition, thereby restoring correct splicing of the pre-mRNA. By addressing two isolated (ABCA4:c.5197-557G>T and USH2A:c.7595-2144A>G) and two clustered (ABCA4:c.5196+1013A>G and ABCA4:c.5196+1056A>G) pathogenic deep-intronic variants, we demonstrated effective splicing rescue in minigene assay employing distinct single gRNAs. Further validation in patient-derived fibroblasts for the common USH2A:c.7595-2144A>G variant confirmed consistent and high splicing correction. Additionally, the characterization of achieved gene editing affirmed the generation of enhanced deletions by EDSpliCE, revealed high directionality of editing events for all the single gRNAs tested in patient-derived fibroblasts and did not show higher off-target editing potential on selected loci. Conclusions: The successful implementation of the EDSpliCE platform for splicing correction and modulation offers a promising and versatile gene editing approach to address splicing defects, potentially providing a safer option to existing gene editing strategies.

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Retinal Organoids from Induced Pluripotent Stem Cells of Patients with Inherited Retinal Diseases: A Systematic Review

Lee,

2024

Stem Cell Rev and Rep

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Background Currently, most inherited retinal diseases lack curative interventions, and available treatment modalities are constrained to symptomatic approaches. Retinal organoid technology has emerged as a method for treating inherited retinal diseases, with growing academic interest in recent years. The purpose of this review was to systematically organize the current protocols for generating retinal organoids using induced pluripotent stem cells from patients with inherited retinal disease and to investigate the application of retinal organoids in inherited retinal disease research. Methods Data were collected from the PubMed, Scopus, and Web of Science databases using a keyword search. The main search term used was “retinal organoid,” accompanied by secondary keywords such as “optic cup,” “three-dimensional,” and “self-organizing.” The final search was conducted on October 2, 2024. Results Of the 2,129 studies retrieved, 130 were included in the qualitative synthesis. The protocols for the generation of retinal organoids in inherited retinal disease research use five major approaches, categorized into 3D and a combination of 2D/3D approaches, implemented with modifications. Disease phenotypes have been successfully reproduced via the generation of retinal organoids from the induced pluripotent stem cells of individuals with inherited retinal diseases, facilitating the progression of research into novel therapeutic developments. Cells have been obtained from retinal organoids for cell therapy, and progress toward their potential integration into clinical practice is underway. Considering their potential applications, retinal organoid technology has shown promise across various domains. Conclusion In this systematic review, we organized protocols for generating retinal organoids using induced pluripotent stem cells from patients with inherited retinal diseases. Retinal organoid technology has various applications including disease modeling, screening for novel therapies, and cell replacement therapy. Further advancements would make this technology a clinically significant tool for patients with inherited retinal diseases. Graphical Abstract

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Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C

Cited by 18 publications

References 62 publications

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

EDSpliCE, a CRISPR-Cas9 gene editing platform to rescue splicing, effectively corrects inherited retinal dystrophy-associated splicing defects

Retinal Organoids from Induced Pluripotent Stem Cells of Patients with Inherited Retinal Diseases: A Systematic Review

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