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Part 2

Research Hypotheses

Computational hypotheses for accelerating STRC gene therapy. These require experimental validation.

AAV packaging

Mini-STRC Hypothesis

A truncated STRC construct (3984 bp) that fits within the AAV packaging limit. Leverages AlphaFold pLDDT to identify dispensable disordered N-terminal domains.

In situ correction

Prime Editing

Precision correction of c.4976A>C using PE3 or PE3b pegRNA strategy without double-strand breaks.

Non-invasive

Sonogenetics

Mechanosensitive channel activation via focused ultrasound. ODE model of calcium signaling in OHC stereocilia.

Sonoporation

Delivery

Non-invasive cochlear gene delivery via sonoporation + LNP. ODE model shows 78% transduction efficiency under optimized parameters.

Stochastic model

Dual-Vector vs Single-Vector

Poisson stochastic model quantifying the probability cost of dual-vector co-transduction vs single-vector strategy.

Biophysics

Electrostatic Analysis

Coulomb energetics explain why E1659A is pathogenic despite intact structure. 8.62 kcal/mol destabilization of adhesion interface.

Pharmacokinetics

Immune Response

NAb kinetics, seroprevalence barriers, and delivery vehicle comparison for cochlear gene therapy re-dosing strategies.