Transthyretin amyloidosis is a rare yet lethal disease caused by an increase in the destabilization of transthyretin tetramer into monomers, leading to amyloid fibril aggregates in tissues. Multiple therapeutics have been developed to limit or halt disease progression by altering tetramer kinetics. Small molecules, like Tafamidis and AG10, stabilize the tetrameric structure while genetic therapies, like Patisiran and NTLA-002, limit the production of TTR protein by silencing genetic expression. Both of these interventions slow the accumulation of fibrils by intervening at different points in the tetramer-monomer-fibril pathway. We developed a mathematical model to compare the pharmacological efficacies of these modalities by comparing each drug's ability to reduce the rate of tetramer to monomer formation, or "tetrameric flux." The model was trained on in vitro tetramer data as well as clinical measurements of tetramer concentration in humans. Overall, genetic silencers reduced tetrameric flux more than small molecule stabilizers. Properties that led to an improvement in small molecule stabilizer function and potential benefit of gene therapy - small molecule combination were explored. This study exemplifies how modeling can be used to compare modalities with differing mechanisms of action.
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