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Anonymous ID: 017215 Aug. 30, 2021, 6:13 p.m. No.14494452   🗄️.is 🔗kun

However, a third study found no such correlation 115 and any causality between decreased ACE2 activity and disease symptoms remains inconclusive. Nonetheless, catalytically active sACE2 offers two potential mechanisms of action. First, it blocks receptor‐binding sites on SARS‐CoV‐2 spikes to neutralize infection. Second, it promotes the degradation of Ang‐II and production of Ang‐1‐7 to directly address COVID‐19 symptoms. A clinical trial testing WT sACE22 in critically ill COVID‐19 patients was recently completed (ClinicalTrials.gov Study NCT04335136; Apeiron Biologics media release 12 March 2021) and suggests, along with a preliminary case report, 67 that both mechanisms of action are at play. This provides sACE2 a tremendous advantage over monoclonal antibodies, which are safe and effective at reducing viral load 116 but do not directly address symptoms in sick patients. However, at this time no direct comparison has been made in animal models of COVID‐19 to evaluate catalytically active vs inactive sACE2, alongside engineered variants with altered S affinity. The hypothesis that sACE2 will have dual mechanisms of action therefore remains unproven.

Anonymous ID: 017215 Aug. 30, 2021, 6:17 p.m. No.14494473   🗄️.is 🔗kun   >>4522

6.  VESICLE‐BASED ACE2 NANOPARTICLE DECOYS

 

While this review has focused on soluble ACE2 receptors and their associated Ig‐fusions, work has also been done utilizing membrane‐anchored ACE2. These decoys are based on cell‐derived vesicles or fabricated nanoparticles derived from cells expressing membrane‐embedded ACE2. 126 , 127 , 128 Extracellular vesicles produced from cells over‐expressing ACE2 together with TMPRSS2—which is required for membrane fusion following ACE2/S binding 21 —were more effective at neutralizing pseudotyped viruses than purified sACE2, perhaps because of inbuilt avidity from high‐density receptor display. 127 TMPRSS2 was required for optimum activity and it is possible bound viruses fused with the vesicles, effectively creating irreversible neutralization. Vesicles have been further functionalized by the use of membranes from monocytes that naturally express cytokine receptors, such that both virus and cytokines are sequestered on the nanoparticle surface. 128 Inhibited cytokine signaling might ameliorate potentially life‐threatening inflammatory responses associated with severe COVID‐19. Cytokine neutralization activity was confirmed in vivo by suppressed inflammation in a lipopolysaccharide‐induced lung injury model in mice. While vesicle‐based nanoparticles are scientifically exciting and show efficacy for virus and cytokine neutralization, they will almost certainly suffer a tortuous regulatory pathway to the clinic due to composition heterogeneity and safety concerns.