️ Episode 10: Targeting the Genome: Guidelines for Antisense Oligonucleotide Therapy Eligibility
In this episode of Base by Base, we explore a transformative study published in The American Journal of Human Genetics that introduces the N1C VARIANT guidelines — a consensus framework for evaluating the eligibility of pathogenic DNA variants for antisense oligonucleotide (ASO) therapies. This pioneering effort addresses a critical gap for rare genetic diseases, where individualized treatments are urgently needed.
Led by Cheerie and colleagues from the N=1 Collaborative, the study outlines a systematic approach to classify variants for ASO strategies such as splice correction, exon skipping, transcript knockdown, and upregulation of wild-type alleles, providing practical tools like eligibility calculators and training materials.
Key insights include:
Development of the N1C VARIANT Guidelines: A structured framework to assess DNA variants for ASO-based therapeutic strategies, with classifications like eligible, likely eligible, unlikely eligible, not eligible, and unable to assess.
Innovative Tools: Creation of an interactive eligibility calculator and educational videos to streamline variant assessment and training.
Multiple ASO Strategies Covered: Guidelines cover not only traditional splice correction and exon skipping but also emerging methods like transcript knockdown and upregulation of the wild-type allele.
Community-Centered Approach: Built through collaboration among international experts and piloted by geneticists, researchers, and clinicians across diverse healthcare settings.
Path to Clinical Integration: Highlights the potential to integrate variant assessments into routine clinical practice, offering rare disease patients a new avenue toward personalized treatment options.
This episode highlights how collaborative, structured frameworks are accelerating the translation of genomic diagnostics into actionable, individualized therapies for rare diseases.
Reference:Cheerie, D., Meserve, M.M., Beijer, D., et al. (2025). Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments. The American Journal of Human Genetics, 112(5), 1–9. https://doi.org/10.1016/j.ajhg.2025.02.017
License: This content is distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). For more information, visit https://creativecommons.org/licenses/by/4.0/
