ActRII Polypeptides for Post-Capillary Pulmonary Hypertension
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Solution Overview
Problem
There is a high unmet need for effective therapies to treat post-capillary pulmonary hypertension (PcPH), particularly in reducing its progression rate and severity, as well as associated complications such as smooth muscle and endothelial cell proliferation, angiogenesis, dyspnea, chest pain, pulmonary vascular remodeling, right and left ventricular hypertrophy, fibrosis, and pulmonary fibrosis.
Innovation Solution
Administering a polypeptide with a specific amino acid sequence, such as ActRII polypeptides, that is highly identical to SEQ ID NO: 1 or SEQ ID NO: 2, to patients with PcPH, which reduces mean pulmonary arterial pressure (mPAP), pulmonary arterial wedge pressure (PAWP), diastolic pressure gradient (DPG), transpulmonary pressure gradient (TPG), and pulmonary vascular resistance (PVR), and decreases ventricular and pulmonary hypertrophy and fibrosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for post-capillary pulmonary hypertension, then treatment of underlying disease is provided, but effective therapy for reducing progression rate and severity of PcPH and its complications is insufficient
Solution Approach 1:
The patent employs parameter changes by administering ActRII polypeptides that specifically bind to activin and GDF11 ligands, thereby changing the biochemical parameters of the pulmonary vascular system. This results in reduced mean pulmonary arterial pressure, decreased pulmonary vascular resistance, and attenuation of smooth muscle and endothelial cell proliferation, directly addressing the progression and severity of PcPH
Solution Approach 2:
The ActRII polypeptide acts as an intermediary molecule that binds to activin and GDF11 ligands, preventing these ligands from exerting their harmful effects on pulmonary vascular cells. This intermediary action blocks the pathological signaling pathways that drive pulmonary hypertension progression, smooth muscle proliferation, and endothelial cell damage
2Object-generated harmful factors
If no specific therapy is administered, then current standard care is maintained, but complications such as smooth muscle and endothelial cell proliferation, angiogenesis, and pulmonary vascular remodeling progress
Solution Approach 1:
The patent applies preliminary anti-action by administering ActRII polypeptides that preemptively block activin and GDF11 ligand binding before these ligands can induce smooth muscle and endothelial cell proliferation. This preventive mechanism stops the pathological processes of angiogenesis and pulmonary vascular remodeling before they fully develop, thereby preventing complications
3Stress or pressure
If existing treatments are used, then general heart failure management is provided, but specific reduction of pulmonary arterial pressure and vascular resistance is insufficient
Solution Approach 1:
The ActRII polypeptide administration induces specific parameter changes in the pulmonary circulation by blocking activin/GDF11 signaling, leading to direct reduction of mean pulmonary arterial pressure and pulmonary vascular resistance. This targeted parameter modification addresses the specific hemodynamic abnormalities of PcPH that are not adequately controlled by general heart failure medications
Data Source
AI summary
In some aspects, the disclosure relates to compositions and methods comprising ActRII polypeptides to treat, prevent, or reduce the progression rate and/or severity of post-capillary pulmonary hypertension (PcPH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PcPH-associated complications.