Journal Article

DZNE-2025-01434

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study.

Cheerie, D. ; Lauffer, M. C. ; Newton, L. ; Amburgey, K. ; Beijer, D.DZNE* ; Haque, B. ; Kalish, B. T. ; Meserve, M. M. ; Oh, R. Y. ; Pan, A. Y. ; Reuter, M. S. ; Szego, M. J. ; Szuto, A. ; N=1 Collaborative (Collaboration Author) ; Aartsma-Rus, A. ; Axford, M. M. ; Deshwar, A. R. ; Dowling, J. J. ; Marshall, C. R. ; Ivakine, Z. ; Synofzik, M.Extern* ; Yu, T. W. ; Costain, G. ; Taylor Tavares, A. L. (Contributor) ; Aartsma-Rus, A. (Contributor) ; Verran, A. S. (Contributor) ; Kaiwar, C. (Contributor) ; Beijer, D. (Contributor)Extern* ; Cheerie, D. (Contributor) ; Sherrill, E. (Contributor) ; Costain, G. (Contributor) ; Newton, L. (Contributor) ; Meserve, M. M. (Contributor) ; Lauffer, M. C. (Contributor) ; Synofzik, M. (Contributor)DZNE* ; Nolen, N. (Contributor) ; Leonard, S. (Contributor) ; Sanders, S. J. (Contributor) ; Yu, T. W. (Contributor)

2025
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.gim.2025.101597

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

Keyword(s): Antisense oligonucleotides ; Experimental therapy ; Inborn genetic disease ; Rare disease

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Springer ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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