Risk Intelligence
Failure Modes / Red Flags
Explicitly pressure-test why first-generation AAV may fail for this program, define kill criteria, and map de-risking experiments.
Why first-generation AAV fails here
Target organ underexposed
Severity
Evidence quality
Moderate
De-risking experiment
Quantitative biodistribution in NHP.
Liver sink too strong
Severity
Evidence quality
Moderate
De-risking experiment
Dose-ranging with liver detargeting control arm.
Dose likely too high
Severity
Evidence quality
Moderate
De-risking experiment
Efficacy-vs-dose inflection study.
Barrier penetration insufficient
Severity
Evidence quality
Low
De-risking experiment
In vivo imaging + compartmental sampling.
Pre-existing antibodies block activity
Severity
Evidence quality
High
De-risking experiment
Serotype panel neutralization survey.
Innate immune activation
Severity
Evidence quality
Moderate
De-risking experiment
Cytokine and complement profiling.
Payload size mismatch
Severity
Evidence quality
High
De-risking experiment
Payload redesign or split strategy.
Poor manufacturability
Severity
Evidence quality
Moderate
De-risking experiment
Upstream yield and QC stress run.
Species translation uncertain
Severity
Evidence quality
Low
De-risking experiment
Cross-species validation ladder.
Post-entry inefficiency
Severity
Evidence quality
Low
De-risking experiment
Cellular trafficking mechanistic assay.