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AAV-mediated long-term TBX18 expression causes cardiac fibrosis and fails to induce pacemaker activity in rodents

Jianan Wang,¹ Mathilde R. Rivaud,¹ Mischa Klerk,¹ Arie R. Boender,¹ Ruud N. Visser,¹ Rinske Sparrius,¹ Hee Young Lee,² Karel van Duijvenboden,¹ Huiling Zhou,¹ Yuting Yang,³ Emiel J.M. Kramer,³ Kyung Ho Park,² Larry C. Park,² Silke Schrödel,⁴ Christian Thirion,⁴ Eric Ehrke-Schulz,⁵ Anja Ehrhardt,⁵ Osne F. Kirzner,³ Klaus Neef,³ Hanno L. Tan,³ Arie O. Verkerk,¹ Vincent M. Christoffels,¹ and Gerard J.J. Boink¹

Published June 11, 2026 - More info

Gene therapy-based biological pacemakers have been proposed as an alternative to their hardware-based counterparts. In this context, short-term ectopic expression of the T-box transcription factor 18 (TBX18) in the ventricle has been reported to generate potent short-term pacemaker function in various animal models. Here, we investigated the impact of adeno-associated virus (AAV)-mediated long-term expression of TBX18, and compared the outcomes to those of the pacemaker ion channel Hcn2. Our findings revealed that CMV-driven ectopic TBX18 expression in mouse hearts led to severe cardiac fibrosis. At lower, non-fibrogenic levels, TBX18 maintained its transcriptional function but failed to induce pacemaker phenotypes. TBX18-expressing cells showed suppressed expression of key working myocardial genes, but the pacemaker gene program was not induced. Electrophysiological studies showed abnormal automaticity in TBX18-expressing cells, combined with prolonged repolarization and various current changes. However, no hyperpolarization-activated funny current was detected. In a complete AV-block rat model, AAV-mediated Hcn2 expression induced robust ectopic pacemaker activity in the presence of isoproterenol, whereas TBX18 expression neither generated such activity nor augmented Hcn2-mediated pacing. In conclusion, at functionally non-fibrogenic levels, TBX18 is neither sufficient nor necessary to induce pacemaker activity. In contrast, Hcn2 generates reliable pacing, making it a more viable candidate for biological pacemaker development.

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