N-of-1 ASO

Development of Patient-Customized N-of-1 Antisense Oligonucleotides for Rare Genetic Diseases

Our research group is pioneering personalized treatment approaches for rare genetic diseases using antisense oligonucleotide (ASO) therapies. ASOs are short, DNA-like molecules designed to modulate RNA and correct or bypass disease-causing mutations. These precision therapeutics hold transformative potential for patients with ultra-rare variants, where conventional drug development is not feasible.

Our goal is to translate laboratory innovation into patient-centred therapies through n-of-1 clinical trials — personalized investigational treatments developed for individual patients based on their unique genetic variants.

Our Approach: From Exon Skipping to Personalized ASOs

We have demonstrated the feasibility of exon skipping therapy across multiple models of Duchenne Muscular Dystrophy (DMD) and related neuromuscular disorders. Building on this foundation, our team designs and tests customized ASOs targeting specific mutations across a spectrum of genetic diseases.

This initiative includes:

• Custom ASO Development: Designing individualized ASOs using in silico prediction tools and empirical validation to restore proper RNA processing or silence toxic gene products.

• Preclinical and Translational Research: Assessing efficacy and safety in cellular and animal models before advancing to compassionate or n-of-1 clinical use.

• Clinical Translation: Partnering with international collaborators to navigate regulatory frameworks for individualized ASO therapies.

FDA Guidance and Regulatory Framework

We closely align our efforts with the FDA’s draft guidance on Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening (SDLT) Diseases, including:

• Clinical Recommendations: Tailored development pathways for unique genetic variants in single patients.

• CMC (Chemistry, Manufacturing, and Controls): Ensuring reproducibility and safety of individualized ASOs under GMP conditions.

• Regulatory Interaction: Early consultation with agencies to streamline IND preparation and review.

• Nonclinical Testing: Focused evaluation of pharmacology, toxicology, and biodistribution to support single-patient IND applications.

Dr. Yokota’s Role in the Global N-of-1 Movement

Dr. Toshifumi (Toshi) Yokota is a core contributor to the international working group shaping the framework for individualized ASO development and clinical translation. As a recognized leader in antisense therapy for neuromuscular diseases, the team collaborates with experts worldwide to establish standards for preclinical validation, regulatory submission, and ethical implementation of n-of-1 genetic therapies.
The lab’s contributions—spanning DG9 peptide–enhanced delivery, machine-learning–assisted ASO design, and patient-customized exon skipping approaches—are helping define best practices for future personalized genetic medicines.

Supporting Our Mission

Advancing n-of-1 ASO therapies requires both scientific innovation and community partnership. Your support helps us move closer to making personalized genetic treatments accessible for all who need them.

To learn more about our work or contribute to this effort, please visit our donation page

Last updated: 7 November, 2025