Consensus guidelines for eligibility assessment of pathogenic variants to antisense oligonucleotide treatments

Abstract

Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The Patient Identification Working Group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic variants towards ASO treatments. We herein present the N1C VARIANT (Variant Assessments towards Eligibility for Antisense Oligonucleotide Treatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as either "eligible", "likely eligible", "unlikely eligible", or "not eligible" in relation to the different approaches, or "unable to assess". We also review key considerations for assessment for upregulation of transcripts from the wildtype allele, an emerging ASO therapeutic strategy. We provide additional tools and training material to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice.