November 11, 2026 — Making Precision Medicine Scalable: Researchers Chart a Path from N-of-1 to N-of-Many Genetic Therapies

New research provides a roadmap for expanding personalized ASO therapies across rare disease populations.

SAN DIEGO, Calif. - Nov. 11, 2026 - A study led by Olivia Kim-McManus, MD, provides evidence that one of the most promising approaches in rare disease medicine, individualized genetic therapies developed for a single patient, may be scalable to larger patient populations.

Published in The American Journal of Human Genetics, the research describes how antisense oligonucleotides (ASOs), precision medicines designed to selectively silence disease-causing genes, could be matched to groups of patients based on shared genetic signatures rather than being developed from scratch for every individual.

The findings address one of the biggest challenges facing the field of precision medicine: how to scale highly personalized therapies beyond a single patient.

"Individualized therapies have shown what's possible for patients with severe genetic diseases - but developing a new treatment for every patient is not a sustainable model," said lead author Olivia Kim-McManus, MD. "Our findings suggest we can use genomic information to identify groups of patients who may benefit from the same therapy, creating a pathway from N-of-1 treatments to therapies that can reach many more people."

Dr. Kim-McManus is director of the Precision Therapeutics Neuro-Interventional Center at Rady Children's Hospital San Diego, Director of Batten Center of Excellence Affiliate Center, principal investigator and physician-scientist at Rady Children's Institute for Genomic Medicine, and associate professor of neurosciences at UC San Diego School of Medicine.

A New Framework for Scaling Precision Medicine

Over the past several years, ASO therapies have emerged as an important option for patients with ultra-rare genetic disorders. These therapies are designed to target and reduce the effects of disease-causing genetic mutations.

Several individualized ASOs have produced meaningful clinical improvements in patients with severe neurological disorders, but each treatment has typically been developed under a specialized "N-of-1" pathway, meaning the therapy is created for a single person.

Researchers set out to determine whether these one-patient treatments could become the foundation for therapies capable of serving broader patient populations.

Their answer: potentially yes.

Turning Shared Genetics into Shared Treatments

The study focused on SCN2A-related disorders, a severe neurogenetic diagnosis that is associated with medically refractory epilepsy, autism spectrum disorder, intellectual disability, and developmental delays.

Instead of targeting a patient's unique mutation directly, researchers developed ASOs that recognize common inherited DNA markers located near the disease-causing gene. These markers, known as haplotypes, act as genetic signposts that distinguish the chromosome carrying the harmful mutation from the healthy copy.

Using whole-genome sequencing and advanced haplotype analysis, researchers can identify which genetic pattern a patient carries and select an ASO designed to target the disease-causing version of the gene while sparing the healthy one.

The approach allows a single therapy to potentially be used by many patients who share the same underlying genetic architecture, even when their individual disease-causing mutations differ.

Early Success Points to Broader Potential

The strategy builds on two individualized ASO therapies previously developed for children with severe SCN2A-related disorders.

In both cases, treatment led to sustained clinical improvements, including substantial reductions in seizures and gains in communication, behavior, mobility, and developmental skills. One child who had previously been unable to walk independently achieved the developmental milestone of independent walking after treatment, featured as a research highlight in Nature.

Researchers then asked a larger question: how many additional patients might benefit from those same therapies?

By analyzing genetic data from 21 individuals with SCN2A-related disorders, the team found that the two existing ASOs could potentially apply to nearly half of the patients studied.

The researchers expanded their analysis using genomic data from more than 2,500 individuals in the international 1000 Genomes Project to identify the most common genetic patterns associated with the SCN2A gene.

They found that a panel of just four haplotype-specific ASOs could potentially provide treatment coverage for more than 76% of individuals carrying relevant SCN2A genetic variants.

Building a Pre-Developed Library of Genetic Medicines

The work introduces a model that resembles other forms of precision medicine already used in oncology, where patients are matched to treatments based on specific biomarkers.

Rather than developing a new ASO each time a patient is diagnosed, researchers envision a future in which a library of pre-designed, pre-characterized therapies is developed in advance for the most common genetic patterns associated with a disease.

Once genome sequencing identifies a patient's specific genetic profile, clinicians could select the most appropriate therapy from that existing toolkit.

Such an approach could significantly shorten development timelines, reduce costs, and allow safety and efficacy data generated in earlier patients to support treatment decisions for future patients.

Implications for Rare Disease Drug Development

Beyond SCN2A, the researchers believe the strategy could be applied to many rare genetic disorders caused by harmful gain-of-function or dominant-negative mutations, including neurological, developmental, metabolic, inflammatory, and immune-related diseases.

The study also arrives as regulators explore new frameworks for evaluating platform-based genetic medicines. Recent FDA guidance has outlined potential pathways for umbrella applications and basket-trial approaches that could support the development of multiple related therapies under a shared mechanism of action.

Taken together, the findings suggest that individualized genetic medicines may not have to remain individualized forever.

Instead, researchers envision a future in which a small number of strategically designed therapies can be matched to large segments of rare disease populations, preserving the precision of personalized medicine while achieving the scale needed for broader clinical impact.

About the Study

The study, "Scaling haplospecific antisense oligonucleotides from N-of-1 to broad use in genetic disease populations by diplotyping," was published in The American Journal of Human Genetics. Research was led by Olivia Kim-McManus, MD, with senior author Stephen Kingsmore, MD, DSc, and colleagues from Rady Children's Institute for Genomic Medicine, University of California San Diego, and Illumina. The work builds on prior individualized ASO treatments developed for children with severe SCN2A-related disorders and proposes a scalable framework that could ultimately be applied across numerous rare genetic diseases.

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