Most genetic medicine is built for populations large enough to support a clinical trial. N-of-1 medicine is built for the opposite case: a single patient whose mutation may never be seen again. In the most recent episode of The Genetics Podcast, host Patrick Short speaks with Dr. Timothy Yu, neurologist and geneticist at Boston Children's Hospital and Harvard Medical School, about how that idea went from a single emergency case to a growing field with its own regulatory pathway.
Tim is best known for leading the team behind milasen, the custom antisense oligonucleotide (ASO) drug created for Mila, a young girl with Batten disease. The conversation traces that story from a Facebook message to where the field stands today: roughly a hundred patients dosed worldwide, a new regulatory framework for individualized genetic drugs, and an expanding toolkit that now includes gene editing alongside ASOs.
In 2017, Tim's lab at Boston Children's had built early expertise in whole genome sequencing to diagnose rare neurologic disease. A family contact reached his wife through Facebook to share that a six-year-old girl in Colorado had a clinical diagnosis of Batten disease but no confirmed genetic cause after standard testing had failed.
Tim's team found the answer within two to three months, identifying a deep intronic mutation that was hidden from standard clinical testing. However, Tim understood this discovery was severely limited by the lack of available treatment.
What changed the trajectory was recognizing that the specific mechanism, a splicing defect, mapped onto ASOs that had just been approved for spinal muscular atrophy. The team designed a custom ASO intended to correct Mila's mutation directly. Tim notes that the science moved faster than expected; the first round of candidate molecules included two that worked well almost immediately. What proved far harder was everything around the science: questions of liability, manufacturing partners unfamiliar with working directly with hospitals, and last-minute negotiations over how the drug could even be labeled for use.
Nine years on, Tim doesn't take the field's growth for granted. His own lab has run four N-of-1 programs treating seven patients, but the broader community, across academic centers and now industry partners, has scaled the approach to an estimated hundred patients worldwide.
He's careful to frame this as still early. Most of these programs are evaluating safety and tolerability rather than confirmed efficacy. Mila herself eventually passed away from her disease, though Tim believes the drug helped slow her most severe symptoms for a period. The next inflection point, he says, will come over the next year or two as more of these small trials read out efficacy data. One program he's currently writing up, in ataxia-telangiectasia, has shown six years without decline across multiple measures, which he considers one of the field's first likely successes.
A recurring theme is how to generate convincing clinical evidence when a treatment will only ever be tested in one or a handful of patients, in diseases that usually lack validated biomarkers or rating scales. Tim describes the approach as needing to extract more signal from less data by combining clinical rating scales, wearable accelerometry data, and biomarkers. Additionally, an individual patient's trajectory can be compared against natural history data for that disease.
Tim credits the Oligonucleotide Therapeutic Society (OTS) with helping launch what became the N-of-1 Collaborative (N1C), an independent nonprofit formed after the milasen experience to support physicians, scientists, industry, and patients working in this space. He describes it partly as a survival mechanism for his own lab, which couldn't field every inquiry it was receiving, and partly as a way to keep the field's collective experience from being relearned program by program.
The N1C has since attracted industry partners, including the n-Lorem Foundation, born out of Ionis, and Servier, which recently began working with n-Lorem. Tim says another large biopharma partnership is in the works.
Patrick asks how Tim weighs continued investment in ASOs against newer tools like gene editing, given that ASOs are estimated to be applicable to only a single-digit percentage of patients. Tim frames the two as complementary rather than competing. ASOs are narrow in applicability but inexpensive to manufacture, highly stable, reversible, and well suited to tissues like the eye, brain, spinal cord, and liver. Editing tools such as base editing and prime editing have much broader theoretical applicability and the prospect of one-time dosing, but carry higher manufacturing costs and off-target considerations that still need to be managed.
Tim points to the case of baby KJ, treated with a custom base-editing therapy for a liver disorder led by Drs. Kiran Musunuru and Rebecca Ahrens-Nicklas, as an example of editing's potential within the N-of-1 model. He also previews a new initiative, a Center for Therapeutic Genetics, formed with collaborators and aimed at extending gene editing tools to more N-of-1 applications across the liver, brain, and kidney.
One of the biggest recent developments in the field, Tim explains, is the FDA's Plausible Mechanisms framework. It builds on a 2021 guidance that allowed individualized ASO programs to proceed on an investigational basis, mostly through academic sponsors. The new framework extends that approach to both ASOs and base editing, and is explicitly written as guidance for industry.
The significance, Tim says, is that it signals the FDA is now thinking about how to commercialize these individualized therapies rather than only permitting them as one-off experiments. The framework allows drugs that correct a well-understood, plausible disease mechanism, such as a DNA defect, to potentially be developed as a family of related molecules without requiring separate approval for each one. The details of how broadly that will apply are still being worked out, but Tim sees it as the step that could make individualized genetic medicine commercially sustainable rather than dependent on philanthropy and research grants.
Asked where the field's real bottleneck lies, Tim points to regulatory and business model questions rather than the science or manufacturing. He describes baby KJ's case, a monogenic liver disorder identifiable through newborn screening, as close to a best-case scenario. Patients are diagnosed early, at a known time, with a clear biomarker, making it possible to build a defined clinical and business vertical around that single indication. Finding more of these self-sustaining verticals, rather than attempting to scale the whole field at once, is the near-term goal.
The conversation closes on how N-of-1 medicine could connect with upstream efforts in rapid genome sequencing for NICU and PICU patients, and presumed-healthy newborn screening programs. Tim says the clearest link today is for liver disorders, where early NICU diagnosis can feed directly into programs like the baby KJ model.
For neurologic conditions, where outcome measures are less standardized, the path is harder to define. Tim's lab recently received an NIH grant to build a registry tracking NICU patients with neurologic findings, connect them to labs developing therapeutics for their specific conditions, and study how well that pathway works in practice. He compares the long-term goal to how children born with serious heart defects already move through an established, customizable surgical pathway without requiring a new approval at every step, and suggests genetic medicine could eventually work toward a similarly integrated model.
Tim Yu's conversation traces N-of-1 genetic medicine from a single emergency case in 2017 to a field with shared infrastructure, an expanding toolkit spanning ASOs and gene editing, and its first dedicated FDA regulatory pathway. The next few years will test whether these therapies can show durable efficacy at scale, and whether the field can identify the specific clinical verticals, like early-diagnosed monogenic liver disease, where a sustainable business and regulatory model can take hold first.
Listen to the full episode below.