Inhibition of BACH1 for pulmonary arterial hypertension therapy

LU 2024-222

INVENTORS

• Youyang Zhao*

SHORT DESCRIPTION

This invention identifies a protein called BACH1 as a key driver of pulmonary arterial hypertension (PAH). By targeting and inhibiting BACH1, particularly in the pulmonary endothelium, this technology provides methods for preventing or reversing the abnormal thickening of pulmonary vasculature, potentially improving heart function and offering a new treatment for PAH.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease characterized by increased pulmonary vascular resistance and extensive remodeling of the pulmonary vasculature, ultimately leading to right heart failure and premature death. Despite existing treatment options, which primarily focus on vasodilation through pathways like prostacyclin, nitric oxide, and endothelin, these therapies offer only limited improvements in disease progression. A significant challenge lies in the incomplete understanding of the fundamental molecular mechanisms that drive the pathological pulmonary vascular remodeling, meaning current approaches largely fail to halt or reverse the underlying structural changes, leaving a high mortality rate and a critical unmet medical need for more effective, disease-modifying treatments.

ABSTRACT

This invention identifies the transcription factor BACH1 as a critical regulator in the pathogenesis of pulmonary arterial hypertension (PAH), specifically in endothelial cells where its expression is significantly elevated in PAH patients and in response to disease-relevant stimuli such as PDGF and hypoxia. Endothelial cell-specific knockout of BACH1, achieved via nanoparticle-mediated CRISPR delivery, markedly reduces pulmonary vascular remodeling, smooth muscle cell proliferation, and right heart dysfunction in preclinical models of PAH. Mechanistically, BACH1 promotes PAH by stabilizing HIF-2α protein and repressing PPARγ expression in endothelial cells. The invention proposes therapeutic strategies to inhibit endothelial BACH1, including small molecule inhibitors, siRNA, antisense oligonucleotides, antibodies, dominant negative forms, and genome editing techniques, to mitigate pulmonary vascular remodeling and treat PAH.

APPLICATIONS

• Development of therapeutics targeting endothelial BACH1 for treating PAH – including small molecules, degraders, siRNAs, antisense oligonucleotides, antibodies, and genome editing techniques.

ADVANTAGES

• Targeting a novel molecular pathway – endothelial BACH1 inhibition addresses a previously unrecognized pathway in PAH, offering a new therapeutic target.
• Potential for disease modification – by directly influencing pulmonary vascular remodeling, inhibiting endothelial BACH1 may offer disease-modifying effects beyond current therapies that focus primarily on symptom management.
• Potential for combination therapy – endothelial BACH1 inhibitors may be combined with existing PAH treatment to enhance efficacy, offering a synergistic approach to improve patient outcomes.

IP STATUS

A US non-provisional patent has been filed.