Abstract 19616: AG10 Stabilizes Pathogenic TTR Variants With High Potency - Potential for an Effective Treatment for TTR Cardiomyopathy
Background: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is caused by misfolding and aggregation of wild type or variant TTR in the heart. Point mutations in TTR promote amyloidogenesis either by lowering its thermodynamic stability or via decreasing the kinetic barrier for tetramer dissociation. Kinetic stabilization of the native tetrameric structure of TTR by small molecules raises the dissociative transition state energy, prevents TTR aggregation and is thought to halt/slow disease progression. AG10 is a potent and selective kinetic stabilizer of TTR that prevents dissociation of TTR tetramers, the initiating event in the pathological cascade leading to organ damage.
Methods: We used a variety of biochemical and cellular assays to evaluate the efficacy of AG10 to stabilize a series of ATTR-CM associated TTR mutations (T60A, L58H, V122I, F64L, P24S, Y114C, D38A) and to protect iPSC-derived human cardiomyocytes from TTR aggregate-mediated cytotoxicity. In addition we explored how TTR aggregates disrupt protein homeostasis and signaling networks in iPSC-derived human cardiomyocytes.
Results: We show that AG10 fully stabilized serum TTR from ATTRwt and ATTRmut CM patients (T60A, L58H, V122I, F64L, P24S, Y114C and D38A). AG10 protected human iPSC-derived cardiomyocytes from TTR aggregate cytotoxicity and disruption of the proteostasis signaling network. Results for the T60A, N38A and F64L variants are shown in Figure 1&2.
Conclusion: We find that AG10 is a potent stabilizer of wild type and pathogenic mutant TTR and protects cardiomyocytes from both disruption of the proteostasis network and cell death initiated by exposure to TTR aggregates.
Author Disclosures: I.A. Graef: Ownership Interest; Significant; Eidos Therapeutics. Y. Lee: None. M. Miller: None. M. Alhamadsheh: Ownership Interest; Significant; Eidos Therapeutics. R. Witteles: None. M. Liedtke: None. U. Sinha: Employment; Significant; Eidos Therapeutics. R. Zamboni: Employment; Significant; Eidos Therapeutics. N. Kumar: Ownership Interest; Significant; Eidos Therapeutics. J. Fox: Employment; Significant; Eidos Therapeutics. D. Judge: None.
- © 2017 by American Heart Association, Inc.