The Genetics Podcast

The episode delivers meaningful technical and regulatory insight - ASO reversibility as a clinical management tool, the 5-20% applicability aperture, the Plausible Mechanisms Framework as an industry-facing regulatory shift - but roughly a third of runtime is biographical narrative and conversational setup that dilutes density.

“They're also reversible. So you can get leeway in running these programs knowing that you can run them in a somewhat exploratory dose ranging basis by titrating the dose up if necessary or pausing if necessary if you reach efficacy earlier than expected or toxicity that you didn't want.”

“you might be allowed to make a family of those drugs that are all closely related to each other, but without having to seek approval for each individual molecule, which is the way that the previous system has always, always worked.”

The cardiac-surgery-as-template analogy for genetic medicine workflows and the framing of ASO reversibility as a dosing-exploration superpower are genuinely fresh; however, most content is expert insider knowledge made accessible rather than counterintuitive or first-principles argumentation.

“Look, there are some kids who are born with serious heart defects that make them eligible for a corrective surgery, right? And we have a system that's in place. It's not an investigational drug...But there is a system that's in place whereby medical professionals...can come in and operate on these kids to correct an underlying, say, heart defect.”

“ASOS where this all started which have narrow applicability, but they're beautiful for some applications like the eye and the brain and the spinal cord and the liver. They do have an additional superpower of being inexpensive to manufacture, easy to ship around, and stable as heck.”

Timothy Yu is the originating practitioner in N-of-1 ASO medicine - he developed Milasen, runs four active programs treating seven patients, co-founded the N1C, and is now building a Center for Therapeutic Genetics with David Liu; this is a working clinician-scientist who has literally done the thing being discussed.

“We've run ourselves four programs treating seven patients to date and have many more coming.”

“It started out of conversations between folks like David Liu and myself and Kieran Musunaro and Becca Aarons, Nicholas...We're starting a new effort that mixes The N of one work that we've worked in for now almost 10 years with the editing work to create what we're calling a center for Therapeutic genetics.”

Strong on named collaborators, timelines, mechanisms, and patient numbers (dozens designed, two candidates worked in two months, ~100 dosed globally, six years of AT follow-up with no decline); weaker on financial figures, quantitative efficacy endpoints, and concrete regulatory timelines.

“We designed a dozen candidates in our first round and found that immediately two of them worked really, really well. And then from those we designed a dozen more.”

“Nupam Gupta, one of our collaborators, has hooked up wrist and ankle sensors to measure accelerometry patterns in these patients and that can be worn and to generate data for days at a time”

The host is clearly knowledgeable and lands a few good targeted questions (the easy-vs-hard framing, the clinical evidence challenge in low-N regimes), but there is no meaningful pushback, several questions are simple setup prompts, and the host's personal grief narrative, while genuine, consumes time without advancing the technical conversation.

“What was easy about it was printing the oligo easy but what, yeah. What was the hard part and what were the easy parts relative to your expectations?”

“Could you tell people who aren't familiar with the framework? It's one of the biggest pieces of regulatory news I think in the last year or so in our space. Yeah. It'd be great if you could talk a little about what you, what the potential is you see there.”