Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study

N1C Moderator
3 days ago
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David Cheerie, Marlen C Lauffer, Logan Newton, Kimberly Amburgey, Danique Beijer, Bushra Haque, Brian T Kalish, Margaret M Meserve, Rachel Y Oh, Amy Y Pan, Miriam S Reuter, Michael J Szego, Anna Szuto; N=1 Collaborative; Annemieke Aartsma-Rus, Michelle M Axford, Ashish R Deshwar, James J Dowling, Christian R Marshall, Zhenya Ivakine, Matthis Synofzik, Timothy W Yu, Gregory Costain

January 28, 2026

Abstract

Purpose

To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.

Methods

We retrospectively applied the N=1 Collaborative’s Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible,” “likely eligible,” “unlikely eligible,” or “not eligible” in relation to the different ASO approaches, or “unable to assess.”

Results

In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.

Conclusion

A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.

Introduction

Rare genetic conditions are major contributors to pediatric morbidity and mortality, but few have specialized treatments.¹^,² Increased access to genome-wide sequencing (GWS) is replacing diagnostic odysseys with therapeutic odysseys.¹^,³ Antisense oligonucleotides (ASOs) are short, synthetic chains of nucleotides that have the potential to target any gene product of interest.⁴ ASOs are versatile in their usage, as they can be used to (1) modulate splicing (induce exon skipping or exon inclusion, or correct aberrant (cryptic) splicing), (2) downregulate transcripts in the case of toxic gain-of-function and dominant-negative variants, and (3) increase protein expression from the wild-type allele (Figure 1).⁴^,⁵ ASOs can be delivered efficiently to the central nervous system (including the retina) via local compartment injection and the liver after systemic treatment. These are tissues commonly affected by genetic conditions.4, 5, 6 At present, 15 ASOs have received US Food and Drug Administration approval to treat genetic conditions (Supplemental Table 1). Proof-of-concept also exists for individualized genetic interventions with ASOs that are customized for specific genetic variants (Crooke ST, Cole T, Carroll JB, et al. Genotypic and phenotypic analysis of 173 patients with extremely rare pathogenic mutations who applied for experimental antisense oligonucleotide treatment; 2024:2024.2008.2005.24310862. medRxiv).7, 8, 9, 10 However, the proportion of molecular genetic diagnoses that might be amenable to treatment with a customized ASO therapy in a real-world phenotypically heterogeneous clinical cohort is unknown.