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PULMONARY DELIVERY OF MRI-1867 (ZEVAQUENABANT) AS AN EFFECTIVE THERAPEUTIC MODALITY IN PULMONARY FIBROSIS

ABSTRACT: Pulmonary fibrosis (PF) is a life-threatening disease in need of effective and safe therapeutic modalities. Overactivity of the endocannabinoid (EC)/cannabinoid receptor 1 (CB1R) system and inducible nitric oxide synthase (iNOS) play distinct roles in the development of PF. Accordingly, we have developed MRI-1867 (zevaquenabant) as a peripherally acting hybrid CB1R/iNOS inhibitor. Systemic administration of MRI-1867 is effective in mitigating experimental PF in mice, and it has completed a Phase 1 clinical trial as an oral formulation. Here, we demonstrated that pulmonary delivery of zevaquenabant at 0.5 mg/kg/day is as effective as systemic delivery of 10 mg/kg/day in mitigating PF. Additionally, it is more targeted, yielding high exposure in the fibrotic lung microenvironment. Pulmonary delivery could further improve safety margins by limiting circulatory distribution to peripheral tissues as a result of the reduced therapeutic dose. Therefore, pulmonary delivery of zevaquenabant emerged as a promising therapeutic modality that attenuates multiple fibroproliferative pathways by simultaneously targeting CB1R and iNOS.

ORGANISM(S): Mus musculus

PROVIDER: GSE273132 | GEO | 2025/06/06

REPOSITORIES: GEO

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Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.

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PULMONARY DELIVERY OF MRI-1867 (ZEVAQUENABANT) AS AN EFFECTIVE THERAPEUTIC MODALITY IN PULMONARY FIBROSIS

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