Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice

Jose M Condor Capcha; Ali Kamiar; Emely Robleto; Ali G Saad; Tengjiao Cui; Amanda Wong; Jason Villano; William Zhong; Andrew Pekosz; Edgar Medina; Renzhi Cai; Wei Sha; Mark J Ranek; Keith A Webster; Andrew V Schally; Robert M Jackson; Lina A Shehadeh

doi:10.1073/pnas.2308342120

Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice

Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2308342120. doi: 10.1073/pnas.2308342120. Epub 2023 Nov 20.

Authors

Jose M Condor Capcha^{1

2}, Ali Kamiar^{1

2}, Emely Robleto^{1

2}, Ali G Saad³, Tengjiao Cui^{4

5}, Amanda Wong⁶, Jason Villano⁶, William Zhong⁷, Andrew Pekosz⁷, Edgar Medina⁸, Renzhi Cai^{2

4

5}, Wei Sha^{4

5}, Mark J Ranek^{9

10}, Keith A Webster^{11

12}, Andrew V Schally^{2

4

5}, Robert M Jackson^{4

5}, Lina A Shehadeh^{1

2}

Affiliations

¹ Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136.
² Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136.
³ Department of Pathology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136.
⁴ Research Service, Miami Veterans Affairs Health System (VAHS), Miami, FL 33125.
⁵ Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine, Miami, FL 33101.
⁶ Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205.
⁷ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD 21205.
⁸ Qualityminds Gesellschaft mit beschränkter Haftung (GmbH), Munchen, Munich 81549, Germany.
⁹ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205.
¹⁰ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21205.
¹¹ Integene International Holdings, Miami, FL 33179.
¹² Baylor College of Medicine, Houston, TX 77030.

Abstract

COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-hACE2tg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-hACE2tg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.

Keywords: ARDS; COVID-19; GHRH-R; Necroptosis; SARS-CoV-2.

MeSH terms

Animals
COVID-19* / pathology
Disease Models, Animal
Female
Inflammation / pathology
Lung / pathology
Male
Mice
Mice, Transgenic
Respiratory Distress Syndrome* / pathology
SARS-CoV-2
Weight Loss

Substances

GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
somatotropin releasing hormone receptor
K-18 conjugate

Abstract

MeSH terms

Substances

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