Based on our lung-selective delivery formulation LNP002, Pantherna created a spatial Tie2 receptor agonist for restoring capillary endothelial function in the lung. Under pathological conditions (e.g., SARS-CoV2 infection, pneumonia) pulmonary blood capillaries become activated by inflammatory signals. These triggers result in loosening intercellular junctions and opening endothelial barrier functions, a pathological hallmark event underlying the onset of vascular permeability and ultimately lung edema development.

With PAN004 Pantherna has developed an mRNA-LNP for cell-selective delivery of a mRNA encoding a Tie2 activator selectively at the site where lung edema occurs and thereby sparing other vascular beds. Local mRNA expression provokes intercellular barrier stabilization and prevents eventually increased vascular permeability. PAN004 is therefore a suitable mRNA therapeutic pharmacologically aiming at the acute phase of ARDS development, a life-threatening clinical condition of unmet medical need emerging with the progression of many different diseases.

Current therapeutic focus

mRNA therapy to treat lung edema in ARDS

Lung edema

Alveolar fluid impairs adequate oxygenation/pulmonary gas exchange resulting in severe hypoxemia

Increased vascular permeability prompts paracellular leakage of protein rich fluid and inflammatory cells from the blood stream into the alveolar space

Pathophysiological consequence of endothelial cell damage and barrier disruption in the blood capillaries of the lung due to various insults

ARDS (Acute Respiratory Distress Syndrome)

Acute critical respiratory insufficiency combined with hyperinflammatory reactions occurring upon infections (pneumonia, COVID-19) and other (trauma, transfusion etc.)

Interstitial and alveolar edema development is the hallmark event for the acute onset of ARDS leading to alveolar-capillary barrier breakdown and fibrosis upon progression

Manifests in devastating clinical condition for patients requiring intensive care medicine including mechanical ventilation/ ECMO etc.

General incidence 5-50 cases /100.000/year; rise in incidence anticipated due to severe COVID-19 association

In the US alone more than 190.000 people are affected per year with a hospital mortality of 48,5%

Role of Angiopoietin-Tie2 signaling pathway

Under physiological conditions the balance of Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) maintains endothelial barrier function through Tie2 signaling

Under pathophysiological conditions antagonizing Ang2 overrules agonistic Ang1 resulting in Tie2 deactivation and loosening endothelial cell junctions

Inhibition of Tie2 by Ang2 ultimately increases vascular permeability and in turn paracellular efflux of cell and fluids from the blood vessels


PAN004 is our lead candidate for an innovative mRNA therapy against lung edema. This candidate refers to an LNP-formulated mRNA, encoding a secreted Angiopoietin-1 protein variant for localized activation of the Tie2 pathway of the pulmonary endothelium when given systemically.
As a consequence, spatial activation of the Tie2 signaling pathways prompts endothelial barrier stabilization and counteracts paracellular vascular leakage.

LNP-formulated PTXmRNA™ for expression of secreted Tie2 agonists and activators as therapeutic proteins in pulmonary endothelial cells

Therapeutic proteins expressed in endothelial cells can act in an autocrine and paracrine manner on Tie2 activation of respective vascular bed

Expression of respective therapeutic protein shifts imbalance back to Tie2 activation and promote barrier stabilization

Spatial mRNA expression in the pulmonary endothelium directs pharmacological action precisely at the place where lung edema occurs

Disease-relevant mRNA delivery proof-of-concept study published