Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1

Boujnouni, Najoua El; Bent, M. Leontien van der; Willemse, Marieke; Hoen, Peter A.C. ‘t; Brock, Roland; Wansink, Derick G.

doi:10.1016/j.omtn.2023.04.010

Cited by 2 publications

(4 citation statements)

References 74 publications

(103 reference statements)

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“…6f ). These preliminary results evaluating ASO adverse effects in vitro are consistent with previous studies on ASO toxicity and off target 27 , 28 .…”

Section: Screening Of Asos That Can Reduce Exon 8a In Favour Of Exon ...supporting

confidence: 90%

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Antisense oligonucleotide therapeutic approach for Timothy syndrome

Chen,

Birey,

et al. 2024

Nature

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Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2–6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

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“…6f ). These preliminary results evaluating ASO adverse effects in vitro are consistent with previous studies on ASO toxicity and off target 27 , 28 .…”

Section: Screening Of Asos That Can Reduce Exon 8a In Favour Of Exon ...supporting

confidence: 90%

“…Moreover, to identify adverse effects of ASOs in human neural cells we measured their toxicity, immunogenicity and off-target effects 27 (Extended Data Fig. 6 ).…”

Section: Screening Of Asos That Can Reduce Exon 8a In Favour Of Exon ...mentioning

confidence: 99%

Antisense oligonucleotide therapeutic approach for Timothy syndrome

Chen,

Birey,

et al. 2024

Nature

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“…In a recent study, Boujnouni et al. 1 compared different types of ASOs targeting the DMPK transcript, a key therapeutic target for myotonic dystrophy type 1 (DM1), a neuromuscular disease. ASOs, differing in sequence, mechanism of action, and chemical modification pattern, were directly compared for induced on- and off-target effects.…”

mentioning

confidence: 99%

“…Boujnouni et al. 1 tested (in DM1 myoblasts) two types of ASOs, blockers and gapmers, in two approaches: targeting a specific DMPK mRNA sequence and the CUG repeat tract. DMPK blockers were inefficient, while repeat gapmers showed limited activity in a therapeutic context and also induced the most substantial deregulation of other CUG-containing transcripts.…”

mentioning

confidence: 99%

All roads lead to cure: Diversity of oligonucleotides in DM1 therapy

Fiszer

2023

Molecular Therapy - Nucleic Acids

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Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1

Cited by 2 publications

References 74 publications

Antisense oligonucleotide therapeutic approach for Timothy syndrome

Antisense oligonucleotide therapeutic approach for Timothy syndrome

All roads lead to cure: Diversity of oligonucleotides in DM1 therapy

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