MoreĪUGUST 2022 An update to earlier Back of the Envelope “Model” to support ARWR $100 (Market Cap $11.6B) price target goal Dec 2023. ARO-MMP7 is a promising new therapeutic candidate for the treatment of IPF. Conclusions: Integrin targeting ligand-conjugated siRNAs potently silence MMP7 expression, limit fibrosis and improve lung function in the rat bleomycin model.
An inhaled dose of a lead candidate silenced 80-90% of lung MMP7 mRNA and protein expression in primates and was similarly active in cultured human lung slices. Reduced fibrosis was accompanied by increased lung compliance and oxygen saturation, reductions in weight loss and improved survival. MMP7 siRNA conjugate treatment silenced MMP7 expression by 60-90% and significantly improved Ashcroft histology scores, limited pro-fibrotic gene expression and collagen deposition, and reduced inflammation (lavage eosinophil and neutrophil counts). Results: Bleomycin injury provoked lung MMP7 overexpression, primarily in KRT17+ aberrant basaloid cells. Lead MMP7 siRNA conjugates were also evaluated in primates and in ex vivo human lung slices.
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Methods: Integrin targeting ligand-conjugated siRNAs specific for silencing MMP7 mRNA were intratracheally delivered to rats prior to bleomycin administration followed by serial evaluation of indices of fibrosis and pulmonary function. We utilized Arrowhead’s pulmonary epithelium-targeted RNAi delivery platform to silence lung MMP7 expression in a rat IPF model. MMP7 activity promotes fibrosis and inflammation but development of traditional selective small molecule inhibitors has been challenging.
Bush (Madison, United States) Introduction: In idiopathic pulmonary fibrosis (IPF), aberrant basaloid cells overexpress matrix metalloproteinase 7 (MMP7), a validated biomarker of disease severity. From discord ipf abstract: Silencing MMP7 expression with a lung-targeted RNAi molecule limits fibrosis and preserves pulmonary function in bleomycin-injured rats T.
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