Inhalation of an RNA aptamer that selectively binds extracellular histones protects from acute lung injury

Beilei Lei; Chaojian Wang; Kamie Snow; Murilo E Graton; Robert M Tighe; Ammon M Fager; Maureane R Hoffman; Paloma H Giangrande; Francis J Miller Jr

doi:10.1016/j.omtn.2023.02.021

Inhalation of an RNA aptamer that selectively binds extracellular histones protects from acute lung injury

Mol Ther Nucleic Acids. 2023 Feb 24:31:662-673. doi: 10.1016/j.omtn.2023.02.021. eCollection 2023 Mar 14.

Authors

Beilei Lei¹, Chaojian Wang¹, Kamie Snow¹, Murilo E Graton^{1

2}, Robert M Tighe¹, Ammon M Fager^{1

3}, Maureane R Hoffman^{4

3}, Paloma H Giangrande⁵, Francis J Miller Jr^{1

6

7}

Affiliations

¹ Department of Medicine, Duke University, Durham, NC 27710, USA.
² São Paulo State University, School of Dentistry, Campus of Aracatuba, São Paulo 16015-050, Brazil.
³ Veterans Affairs Medical Center, Durham, NC 27705, USA.
⁴ Department of Pathology, Duke University, Durham, NC 27710, USA.
⁵ Wave Life Sciences, Cambridge, MA 02138, USA.
⁶ Veterans Affairs Tennessee Valley Healthcare, Nashville, TN 37212, USA.
⁷ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.

Abstract

Acute lung injury (ALI) is a syndrome of acute inflammation, barrier disruption, and hypoxemic respiratory failure associated with high morbidity and mortality. Diverse conditions lead to ALI, including inhalation of toxic substances, aspiration of gastric contents, infection, and trauma. A shared mechanism of acute lung injury is cellular toxicity from damage-associated molecular patterns (DAMPs), including extracellular histones. We recently described the selection and efficacy of a histone-binding RNA aptamer (HBA7). The current study aimed to identify the effects of extracellular histones in the lung and determine if HBA7 protected mice from ALI. Histone proteins decreased metabolic activity, induced apoptosis, promoted proinflammatory cytokine production, and caused endothelial dysfunction and platelet activation in vitro. HBA7 prevented these effects. The oropharyngeal aspiration of histone proteins increased neutrophil and albumin levels in bronchoalveolar lavage fluid (BALF) and precipitated neutrophil infiltration, interstitial edema, and barrier disruption in alveoli in mice. Similarly, inhaling wood smoke particulate matter, as a clinically relevant model, increased lung inflammation and alveolar permeability. Treatment by HBA7 alleviated lung injury in both models of ALI. These findings demonstrate the pulmonary delivery of HBA7 as a nucleic acid-based therapeutic for ALI.

Keywords: MT: Oligonucleotides: Therapies and Applications; RNA aptamer; endothelial cells; histones; lung injury; particulate matter.; smoke inhalation.