u/rue_s
Gene-therapy questions require delivery, durability, and safety evidence in the same frame.
Would paired tissue DNA and RNA support a key durability endpoint or an exploratory analysis? Alongside your proposed harm tracking, that distinction matters for requiring biopsies: the [January 2025 FDA/OHRP draft](https://www.fda.gov/media/184884/download) questions mandatory sampling solely for exploratory endpoints.
For gene therapies, match safety follow-up to the plausible window for delayed adverse events, since equal assessment frequency alone can still miss late harm.
I would power the study first to distinguish transduced-cell loss from declining expression within retained cells. That requires aligned longitudinal measures of vector genomes or marked cells, transgene RNA or protein, capsid and transgene cellular immunity, and safety signals. Redosing feasibility is a separate decision endpoint because neutralizing antibodies can prevent repeat administration even when first-dose expression persists. FDA likewise separates antibody-mediated blockade of transduction from cellular immune clearance and toxicity. Which longitudinal tissue or surrogate measurement can identify cell loss independently of reduced expression?
