Rescue of mis-splicing of a common SLC26A4 mutant associated with sensorineural hearing loss by antisense oligonucleotides

Feng, Pengchao; Xu, Zhijiao; Chen, Jialin; Liu, Meizhen; Zhao, Yu; Wang, Daqi; Lei, Han; Wang, Li; Wan, Bo; Xu, Xingshun; Li, Dali; Shu, Yilai; Hua, Yimin

doi:10.1016/j.omtn.2022.03.015

Cited by 9 publications

(8 citation statements)

References 43 publications

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“…We excluded SSOs that were fully within the exon or overlapping the splice site. We found and analyzed nine such events where SSOs were identified and confirmed to modulate the splicing of the target exon (Liu et al, 2017 ; Feng et al, 2022 ; Lim et al, 2020 ; Han et al, 2020 ; Hua et al, 2008 ; Kim et al, 2022 ; Centa et al, 2020 ). We applied our XGboost model to these events to retrospectively validate the model as well as identify the SFs likely to regulate the SSO function.…”

Section: Resultsmentioning

confidence: 99%

Development and validation of AI/ML derived splice-switching oligonucleotides

Fronk,

Manzanares,

Zheng

et al. 2024

Mol Syst Biol

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Splice-switching oligonucleotides (SSOs) are antisense compounds that act directly on pre-mRNA to modulate alternative splicing (AS). This study demonstrates the value that artificial intelligence/machine learning (AI/ML) provides for the identification of functional, verifiable, and therapeutic SSOs. We trained XGboost tree models using splicing factor (SF) pre-mRNA binding profiles and spliceosome assembly information to identify modulatory SSO binding sites on pre-mRNA. Using Shapley and out-of-bag analyses we also predicted the identity of specific SFs whose binding to pre-mRNA is blocked by SSOs. This step adds considerable transparency to AI/ML-driven drug discovery and informs biological insights useful in further validation steps. We applied this approach to previously established functional SSOs to retrospectively identify the SFs likely to regulate those events. We then took a prospective validation approach using a novel target in triple negative breast cancer (TNBC), NEDD4L exon 13 (NEDD4Le13). Targeting NEDD4Le13 with an AI/ML-designed SSO decreased the proliferative and migratory behavior of TNBC cells via downregulation of the TGFβ pathway. Overall, this study illustrates the ability of AI/ML to extract actionable insights from RNA-seq data.

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Section: Resultsmentioning

confidence: 99%

Development and validation of AI/ML derived splice-switching oligonucleotides

Fronk,

Manzanares,

Zheng

et al. 2024

Mol Syst Biol

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“…Similarly, the full length of SLC26A4 exon 8 was rescued by ASO-1029 treatment in a homozygous patient-derived peripheral blood mononuclear cell line harboring the c.919-2A>G mutation. Feng et al [129] also reported a successful correction of the missplicing mutation in Slc26a4 in a humanized mice model via the exon inclusion method. Recently, a study developed a combination of ASOs and the CRISPR-Cas9 system to target the CLRN1 mutation at the mRNA and genomic DNA level, respectively.…”

Section: Splice-switching Asosmentioning

confidence: 99%

Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss

Lye,

Delaney,

Leith

et al. 2023

Biomedicines

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Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing. The most common type of hearing impairment is sensorineural hearing loss caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves in the inner ear. There is currently no cure for hearing loss. However, emerging frontier technologies such as gene, drug or cell-based therapies offer hope for an effective cure. In this review, we discuss the current therapeutic progress for the treatment of hearing loss. We describe and evaluate the major therapeutic approaches being applied to hearing loss and summarize the key trials and studies.

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“…While ssASOs are currently mainly used for skipping canonical or cryptic exons, they can also be employed for exon inclusion. Only limited examples of successful exon inclusion are published, such as the inclusion of exon 7 into the SMN2 transcript (NM_017411.4) for the treatment of patients with spinal muscular atrophy, inclusion of exon 2 in GAA (NM_000152.5) for a recurring variant causing Pompe disease, or inclusion of exon 8 for a common SLC26A4 (NM_000441.2) variant causing sensorineural hearing loss [45][46][47].…”

Section: Toxic Gain-of-function and Dominant-negative Variantsmentioning

confidence: 99%

Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

Zardetto,

Lauffer,

van Roon-Mom

et al. 2024

Human Mutation

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Although around 6% of the world’s population is affected by rare diseases, only a small number of disease-modifying therapies are available. In recent years, antisense oligonucleotides (ASOs) have emerged as one option for the development of therapeutics for orphan diseases. In particular, ASOs can be utilized for individualized genetic treatments, addressing patients with a known disease-causing genetic variant, who would otherwise not be able to receive therapy. Careful prioritization of genetic variants amenable to an ASO approach is crucial to increase chances for successful treatments and reduce costs and time for drug development. At present, there is no consensus on how to systematically approach this selection procedure. Here, we present practical guidelines to evaluate disease-causing variants and standardize the process of selecting n-of-1 cases. We focus on variants leading to a loss of function in monogenic disorders and consider which splice-switching ASO-mediated treatments are applicable in each case. To ease the understanding and application of our guidelines, we created a hypothetical transcript covering different pathogenic variants and explained their evaluation in detail. We support our recommendations with real-life examples and add further considerations to be applied to specific cases to provide a comprehensive framework for selecting eligible variants.

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Rescue of mis-splicing of a common SLC26A4 mutant associated with sensorineural hearing loss by antisense oligonucleotides

Cited by 9 publications

References 43 publications

Development and validation of AI/ML derived splice-switching oligonucleotides

Development and validation of AI/ML derived splice-switching oligonucleotides

Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss

Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

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