Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

Abstract

Although around 6% of the world's population is affected by rare diseases, only a small number of disease-modifying therapies are available. In recent years, antisense oligonucleotides (ASOs) have emerged as one option for the development of therapeutics for orphan diseases. In particular, ASOs can be utilized for individualized genetic treatments, addressing patients with a known disease-causing genetic variant, who would otherwise not be able to receive therapy. Careful prioritization of genetic variants amenable to an ASO approach is crucial to increase chances for successful treatments and reduce costs and time for drug development. At present, there is no consensus on how to systematically approach this selection procedure. Here, we present practical guidelines to evaluate disease-causing variants and standardize the process of selecting n-of-1 cases. We focus on variants leading to a loss of function in monogenic disorders and consider which splice-switching ASO-mediated treatments are applicable in each case. To ease the understanding and application of our guidelines, we created a hypothetical transcript covering different pathogenic variants and explained their evaluation in detail. We support our recommendations with real-life examples and add further considerations to be applied to specific cases to provide a comprehensive framework for selecting eligible variants.