Development of an aerosol intervention for COVID-19 disease: Tolerability of soluble ACE2 (APN01) administered via nebulizer.

As ACE2 is the critical SARS-CoV-2 receptor, we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung, and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here, after demonstrating in vitro neutralization of SARS-CoV-2 by APN01, and after obtaining preliminary evidence of its tolerability and preventive efficacy in a mouse model, we pursued development of an aerosol formulation. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization.

Development of a novel, pan-variant aerosol intervention for COVID-19.

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways.

A robust protocol for regional evaluation of methacholine challenge in mouse models of allergic asthma using hyperpolarized 3He MRI.

Hyperpolarized (HP) (3)He magnetic resonance imaging has been recently used to produce high-resolution images of pulmonary ventilation after methacholine (MCh) challenge in mouse models of allergic inflammation. This capability presents an opportunity to gain new insights about these models and to more sensitively evaluate new drug treatments in the pre-clinical setting. In the current study, we present our initial experience using two-dimensional (2D), time-resolved (3)He MRI of MCh challenge-induced airways hyperreactivity (AHR) to compare ovalbumin-sensitized and challenged (N = 8) mice to controls (N = 8).

Ventilation-synchronous magnetic resonance microscopy of pulmonary structure and ventilation in mice.

Increasing use of transgenic animal models for pulmonary disease has raised the need for methods to assess pulmonary structure and function in a physiologically stable mouse. We report here an integrated protocol using magnetic resonance microscopy with gadolinium (Gd)-labeled starburst dendrimer (G6-1B4M-Gd, MW = 192 +/- 1 kDa, R(h) = 5.50 +/- 0.

Dynamic lung morphology of methacholine-induced heterogeneous bronchoconstriction.

Hyperpolarized (HP) 3helium (3He) dynamic MRI was used to investigate airway response in rats following intravenous (i.v.) bolus administration of a contractile agent, methacholine (MCh).

Measurement of regional lung function in rats using hyperpolarized 3helium dynamic MRI.

Dynamic regional lung function was investigated in rats using a radial acquisition cine (RA-CINE) pulse sequence together with hyperpolarized (HP) (3)He gas delivered by a constant flow ventilator. Based on regional differences in the behavior of inspired air, the lung was conceptually divided into two regions (the major airways and the peripheral airspace) for purposes of functional analysis. To measure regional function in the major airways, a large RF flip angle (24 degrees) was applied to reduce (3)He magnetization in the peripheral airspace, and signal intensity (SI) was normalized with the projected airway diameter to estimate local airflow.