![]() ![]() The following image shows the robust induction of MMP7 expression following a dose of bleomycin. The rat bleomycin model of IPF causes MMP7 expression to dramatically increase following exposure of rats to bleomycin. Unfortunately, MMP7 is a difficult target for drug development as there is substantial domain homology with other MMPs, thus making gene silencing a potentially useful mechanism for downregulating MMP7 expression. ![]() In addition, MMP7 knockout mice are protected from pulmonary fibrosis induced by intratracheal bleomycin ( Zuo et al., 2002). ![]() It is useful as a biomarker due to its increased expression being correlated with disease progression. The decrease in MUC5AC mRNA expression results in a substantial decrease in MUC5AC protein expression.ĪRO-MMP7: Matrix metalloproteinase 7 (MMP7) is a secreted endopeptidase that is highly overexpressed in patients with idiopathic pulmonary fibrosis (IPF) ( Bauer et al., 2017). The figure on the right shows the results of immunohistochemistry (IHC) in which MUC5AC protein is stained red. Animals treated with a MUC5AC reduction vector results in a reduction in MUC5AC mRNA expression by approximately 70-90% (similar results are seen in cynomolgus monkeys). ![]() In a mouse model of allergic asthma, which utilizes house dust mites (HDM) and IL-13, exposure to allergens the mice have been sensitized to results in a large increase in MUC5AC expression, as shown in the following figure on the left. The protein plays a role in asthma pathogenesis based on results from ovalbumin sensitization and challenge studies ( Evans et al., 2015). As shown in MUC5AC knockout mice, it is not required for normal mucociliary transport or anti-bacterial defense ( Roy et al., 2014). MUC5AC is a mucin protein that is upregulated in the airway of asthmatic patients ( Bonser et al., 2017). In a rat model of allergic asthma, this sustained knockdown of RAGE expression resulted in a decrease in the inflammatory cytokines MIP1a, IL-13, and IP-10 along with decreased recruitment of eosinophils and neutrophils.ĪRO-MUC5AC: This targets expression of MUC5AC in bronchial epithelium. The following figure shows that a single inhaled 0.5 mg/kg inhaled dose of ARO-RAGE results in deep and sustained reduction in the expression of RAGE mRNA in the lung and sRAGE protein in the serum, which lasted at least through 60 days. A soluble form of the protein (sRAGE) found in the serum can be utilized as an easily measured biomarker to monitor for target knockdown. RAGE is required for an allergic airway inflammatory response through release of IL-33 into the airway and it acts upstream of IL-5 and IL-13 ( Oczypok et al., 2015). Single nucleotide polymorphisms in the human gene for RAGE are associated with an increased incidence of asthma. A copy of the presentation can be accessed here.ĪRO-RAGE: This targets the receptor for advanced glycation end-products (RAGE). In May 2022, Arrowhead held a pulmonary R&D day to provide additional information on the company’s pulmonary targeted development candidates ARO-RAGE, ARO-MUC5A, and the previously undisclosed ARO-MMP7. The single ascending dose portion of the study will include three sequentially enrolled NHV cohorts while the multiple ascending dose portion of the study will include three NHV cohorts and two asthma patient cohorts. The single ascending dose portion of the study will include four sequentially enrolled NHV cohorts while the multiple ascending dose portion of the study will include four NHV cohorts and two asthma cohorts.ĪROMUC5AC-1001 is a randomized, double blind, placebo controlled study in up to 42 NHVs and up to 16 patients with moderate-to-severe asthma ( NCT05292950). (NASDAQ:ARWR) announced the first subjects were dosed in two Phase 1/2a clinical trials of ARO-RAGE and ARO-MUC5AC, which are the company’s investigational candidates designed as potential treatments for various muco-obstructive and inflammatory pulmonary diseases.ĪRORAGE-1001 is a randomized, double blind, placebo controlled study in up to 64 normal healthy volunteers (NHVs) and up to 16 patients with mild-to-moderate asthma ( NCT05276570). In July 2022, Arrowhead Pharmaceuticals, Inc. Phase 1/2a Clinical Trials Underway for Pulmonary Disease Candidates ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |