US regulatory officials published a 'plausible mechanism pathway' in The New England Journal of Medicine proposing an expedited approval route for bespoke therapies for ultra-rare diseases. The paper, authored by CBER director Vinay Prasad and FDA's Martin Makary, draws on the n-of-1 CRISPR treatment delivered to an infant (the 'KJ' case) as precedent. The proposal would permit approvals when a clear molecular mechanism is demonstrated but randomized trials are infeasible. The article synthesizes input from patients, clinicians and developers, and cites the need to balance rapid access with patient safety. It explicitly frames criteria for therapies based on specific molecular abnormalities rather than broad diagnostic categories. Experts quoted in the piece — including proponents for streamlined routes for advanced autologous medicines — signal the agency is testing policy levers to accelerate personalized interventions. For developers of bespoke gene and cell therapies, the pathway could lower regulatory barriers for single-patient or very small-cohort trials but will raise new questions about evidence thresholds, manufacturing oversight and post-approval monitoring. Regulators and industry stakeholders will now need to translate the pathway's conceptual framework into concrete guidance documents and trial designs.