# From Genomic Diagnosis to Personalized RNA Medicine: Advances in Next-Generation Sequencing and N-of-1 Antisense Oligonucleotide Therapies for Rare Genetic Diseases

## TL;DR

New sequencing and RNA therapies are enabling personalized treatments for rare genetic diseases by linking diagnosis to customized drugs.

## Contribution

The paper reviews how NGS and ASO technologies are being combined to enable N-of-1 therapies for rare genetic disorders.

## Key findings

- NGS and RNA sequencing help identify splicing errors that can be corrected with ASOs.
- N-of-1 ASO therapies like Milasen and Atipeksen demonstrate the feasibility of personalized RNA medicine.
- Challenges remain in delivery, long-term efficacy, and access, but emerging tools like AI and long-read sequencing offer promise.

## Abstract

Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype–phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies—customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches—including long-read sequencing, AI-driven oligo design, and improved delivery—promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases.