TY - JOUR
T1 - Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure
AU - Alogna, Alessio
AU - Berboth, Leonhard
AU - Faragli, Alessandro
AU - Ötvös, Jens
AU - lo Muzio, Francesco Paolo
AU - di Mauro, Vittoria
AU - Modica, Jessica
AU - Quarta, Eride
AU - Semmler, Lukas
AU - Deißler, Peter Maximilian
AU - Berger, Yannic Wanja
AU - Tran, Khai Liem
AU - de Marchi, Beatrice
AU - Longinotti-Buitoni, Gianluigi
AU - Degli Esposti, Lorenzo
AU - Guillot, Etienne
AU - Bazile, Didier
AU - Iafisco, Michele
AU - Dotti, Alessandro
AU - Bang, Marie Louise
AU - de Luca, Claudio
AU - Brandenberger, Christina
AU - Benazzi, Louise
AU - di Silvestre, Dario
AU - de Palma, Antonella
AU - Primeßnig, Uwe
AU - Hohendanner, Felix
AU - Perna, Simone
AU - Buttini, Francesca
AU - Colombo, Paolo
AU - Mühlfeld, Christian
AU - Steendijk, Paul
AU - Mauri, Pierluigi
AU - Tschöpe, Carsten
AU - Borlaug, Barry
AU - Pieske, Burkert M.
AU - Attanasio, Philipp
AU - Post, Heiner
AU - Heinzel, Frank R.
AU - Catalucci, Daniele
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/1/2
Y1 - 2024/1/2
N2 - Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.
AB - Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.
KW - heart failure with reduced ejection fraction
KW - inhalation therapy
KW - L-type calcium channel
KW - microparticle
KW - nanoparticle
KW - peptide
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U2 - 10.1016/j.jacc.2023.10.029
DO - 10.1016/j.jacc.2023.10.029
M3 - Article
C2 - 38171710
AN - SCOPUS:85180596571
SN - 0735-1097
VL - 83
SP - 47
EP - 59
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 1
ER -