The peptide GHRH receptor antagonist MIA-602 reduced lung inflammation, normalized breathing, and protected the heart from injury in mice infected with a SARS-CoV-2 surrogate virus.
Normalized necroptosis markers ZBP1 and pMLKLMIA-602 treatment blocked the key inflammatory cell death pathway (necroptosis) driving tissue destruction in COVID-19-infected mice, while also recovering weight and breathing function.
What the researchers found
Daily subcutaneous MIA-602 treatment in rVSV-SARS-CoV-2-infected K18-hACE2 transgenic mice produced: weight recovery (vs. continued loss in vehicle group), reduced lung perivascular inflammation and pneumonia, decreased ICAM-1 expression in both lung and heart tissue, rescued respiratory rate and normalized airflow parameters (Penh, Rpef, expiratory parameters), and normalized inflammation and necroptosis markers (ZBP1, pMLKL) that were heightened by infection. RNASeq analysis confirmed an anti-inflammatory and pro-survival mechanism of action. The rVSV-SARS-CoV-2 model showed similar pathology to native SARS-CoV-2 infection (~60% infectivity).
Why it matters
Despite vaccines, severe COVID-19 and other respiratory virus infections continue to cause significant morbidity and mortality. Current treatments are limited. MIA-602 represents a peptide-based approach that addresses the inflammatory cascade driving lung damage rather than targeting the virus itself — making it potentially useful across different respiratory infections. The additional heart protection is clinically important since cardiac complications are a major cause of COVID-related death.
How the study worked
K18-hACE2 transgenic mice (which express the human ACE2 receptor) were infected with either native SARS-CoV-2 or BSL-2-compliant rVSV-eGFP-SARS-CoV-2-Spike virus. Model validation confirmed similar patterns of weight loss, infectivity, and histopathology between the two. Infected mice (n=7-8 per group) received daily subcutaneous MIA-602 or vehicle. Unrestrained plethysmography measured respiratory function on days 0, 3, and 5. At day 5, tissues were collected for histopathology, protein/gene expression, and RNASeq analysis.
What this study cannot tell us
Mouse model with a surrogate virus — while validated against native SARS-CoV-2, it may not fully replicate human COVID-19 pathophysiology. The 5-day study period is very short. Group sizes (7-8 mice) are modest. The study assessed acute injury prevention but not long-term outcomes. Optimal dosing, timing of treatment initiation, and safety profile in the context of active infection need further characterization.
How to read the evidence
Published in PNAS, this is a well-designed preclinical study using a validated viral infection model with multiple outcome measures including plethysmography, histopathology, and RNASeq. However, it remains an animal study with a short time course and modest group sizes.
When this study was published
Published in 2023 in PNAS, this study demonstrates an innovative application of GHRH receptor antagonist peptides to infectious disease at a time when new COVID treatment approaches are still needed.
The bigger picture
GHRH receptor antagonists like MIA-602 have been studied primarily as anti-cancer peptides, but their immunomodulatory properties are opening new therapeutic areas. This PNAS paper extends the potential of MIA-602 to infectious disease — a significant expansion. The finding that it blocks necroptosis (inflammatory cell death) connects it to a broader understanding of how organ damage occurs in severe infections and suggests applications beyond COVID-19.
Questions still open
- Would MIA-602 be effective when treatment is started after the onset of symptoms rather than at the time of infection?
- Could MIA-602's anti-inflammatory mechanism apply to other respiratory viruses like influenza or RSV?
- What is the therapeutic window for MIA-602 treatment — how late in the disease course can it still provide benefit?
Common questions
What is MIA-602 and how could it help with COVID-19?
Could GHRH receptor antagonists treat other respiratory infections beyond COVID?
Read the original research
Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.
Proceedings of the National Academy of Sciences of the United States of America, 120(48), e2308342120
Citation
Condor Capcha, Jose M; Kamiar, Ali; Robleto, Emely; Saad, Ali G; Cui, Tengjiao; Wong, Amanda; Villano, Jason; Zhong, William; Pekosz, Andrew; Medina, Edgar; Cai, Renzhi; Sha, Wei; Ranek, Mark J; Webster, Keith A; Schally, Andrew V; Jackson, Robert M; Shehadeh, Lina A. (2023). Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.. Proceedings of the National Academy of Sciences of the United States of America, 120(48), e2308342120. https://doi.org/10.1073/pnas.2308342120