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

David Cheerie¹, Marlen C Lauffer², Logan Newton¹, Kimberly Amburgey³, Danique Beijer⁴, Bushra Haque⁵, Brian T Kalish⁶, Margaret M Meserve⁷, Rachel Y Oh⁸, Amy Y Pan¹, Miriam S Reuter⁸, Michael J Szego⁹, Anna Szuto¹⁰; N=1 Collaborative; Annemieke Aartsma-Rus², Michelle M Axford¹¹, Ashish R Deshwar¹², James J Dowling¹³, Christian R Marshall¹¹, Zhenya Ivakine¹⁴, Matthis Synofzik⁴, Timothy W Yu¹⁵, Gregory Costain¹⁶

Collaborators, Affiliations

Collaborators

N=1 Collaborative:
Ana Lisa Taylor Tavares, Annemieke Aartsma-Rus, Aubrie Soucy Verran, Charu Kaiwar, Danique Beijer, David Cheerie, Emma Sherrill, Gregory Costain, Logan Newton, Margaret M Meserve, Marlen C Lauffer, Matthis Synofzik, Nicole Nolen, Stefanie Leonard, Stephan J Sanders, Timothy W Yu

Affiliations

¹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Dutch Center for RNA Therapeutics, Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada.
⁴ Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA.
⁷ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
⁸ Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Department of Family and Community Medicine, University of Toronto, ON, Canada.
¹⁰ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹² Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; Program in Developmental and Stem Cell Biology, SickKids Research Institute, Toronto, ON, Canada.
¹³ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
¹⁴ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
¹⁶ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, SickKids Research Institute, Toronto, ON, Canada. Electronic address: gregory.costain@sickkids.ca.

PMID: 41090344
DOI: 10.1016/j.gim.2025.101597

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

David Cheerie et al. Genet Med. 2025.

. 2025 Oct 11;28(1):101597.

doi: 10.1016/j.gim.2025.101597. Online ahead of print.

Authors

Collaborators

N=1 Collaborative:
Ana Lisa Taylor Tavares, Annemieke Aartsma-Rus, Aubrie Soucy Verran, Charu Kaiwar, Danique Beijer, David Cheerie, Emma Sherrill, Gregory Costain, Logan Newton, Margaret M Meserve, Marlen C Lauffer, Matthis Synofzik, Nicole Nolen, Stefanie Leonard, Stephan J Sanders, Timothy W Yu

Affiliations

¹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Dutch Center for RNA Therapeutics, Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada.
⁴ Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA.
⁷ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
⁸ Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Department of Family and Community Medicine, University of Toronto, ON, Canada.
¹⁰ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹² Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; Program in Developmental and Stem Cell Biology, SickKids Research Institute, Toronto, ON, Canada.
¹³ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
¹⁴ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
¹⁶ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; The Centre for Applied Genomics, SickKids Research Institute, Toronto, ON, Canada. Electronic address: gregory.costain@sickkids.ca.

PMID: 41090344
DOI: 10.1016/j.gim.2025.101597

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.

Keywords: Antisense oligonucleotides; Experimental therapy; Inborn genetic disease; Rare disease.

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Conflict of Interest The authors declare no conflicts of interest.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources