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Compositions and methods relating to treatment of pulmonary arterial hypertension

A technology for lung disease and pulmonary fibrosis, applied in chemical instruments and methods, drug combinations, animal/human proteins, etc.

Active Publication Date: 2022-05-13
THE BRIGHAM & WOMEN S HOSPITAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Inhibition of TGF-β signaling has been attempted for the treatment of pulmonary arterial hypertension, but existing strategies (e.g., inhibition of activin / TGF-β type I kinase receptors ALK4 / ALK5 / ALK7 or nonselective and) cause serious side effects such as hemorrhagic valvular necrosis or abnormalities in bone mineralization and maturation, or significant side effects such as rashes and skin lesions, epistaxis or bleeding gums

Method used

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  • Compositions and methods relating to treatment of pulmonary arterial hypertension
  • Compositions and methods relating to treatment of pulmonary arterial hypertension
  • Compositions and methods relating to treatment of pulmonary arterial hypertension

Examples

Experimental program
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Embodiment 1

[0126] Pulmonary hypertension was induced by treating rats with monocrotaline (MCT). Right ventricular systolic pressure (RVSP, Figure 1A ) and right ventricular hypertrophy (RVH, Figure 1B ) changes are measured. RVSP was measured by right ventricular catheterization and RVH was determined by the ratio of right ventricular (RV) free wall weight to the sum of left ventricular and septal walls (LV+S) (n=3 per time point). Quantitative RT-PCR of the lungs of MCT-treated rats showed increased PAI-1 transcriptional activity ( Figure 1C ) and TGFb1 transcriptional activity ( Figure 1D ) reflected increased TGF-β signaling. By lowering ld1( Figure 1E ) and BMPR2 ( Figure 1F ) mRNA levels showing impaired BMP signaling activity. The expression of TGFb3 in the lungs of MCT-treated rats remained unaffected ( Figure 1G ). GDF15 levels were elevated in the lungs of MCT-treated rats ( Figure 1H ). *p<0.05 and **p<0.01 compared to control rats.

[0127] Use RNA-Seq as an ...

Embodiment 2

[0141] Example 2: Selective TGF-β ligand capture agent improves pulmonary hypertension

[0142] Transforming growth factor-beta (TGF-beta) ligands serve as key regulators of development and tissue homeostasis, signaling through type I and type II serine-threonine kinase receptors to regulate transcriptional programs. Excessive TGF-β signaling and associated transcriptional and remodeling activities implicated in the pathogenesis of pulmonary arterial hypertension (PAH) based on immunohistological and gene expression studies, and TGF-β type I receptor (ALK5) inhibitor attenuation experiments capacity for sexual PAH. However, the therapeutic potential is limited by cardiovascular and systemic toxicity associated with broad inhibition of TGF-β ligands. In this study, we investigated whether a selective TGF-β1 / 3 ligand capture agent (TGFBRII-Fc) could affect experimental PAH and pulmonary vascular remodeling. Treatment with TGFBRII-Fc attenuated SMAD2 phosphorylation, normalized...

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Abstract

The technology described herein is directed to compositions and methods for treating hypertension, such as pulmonary arterial hypertension, related to inhibition of TGF [beta] 1, TGF [beta] 3, and / or GDF-15.

Description

[0001] This application is a divisional application of the application number 201580053901.X with an application date of August 3, 2015 and an invention title of "composition and method related to the treatment of pulmonary arterial hypertension". [0002] Cross References to Related Applications [0003] Pursuant to 35 U.S.C. 119(e), this application claims the benefit of U.S. Provisional Patent Application No. 62 / 031,924, filed August 1, 2014, the contents of which are hereby incorporated by reference in their entirety. [0004] governmental support [0005] This invention was made with government support under 5K08HL07994305 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. technical field [0006] The technology described herein relates to the treatment of fibrosis and / or hypertension (e.g., pulmonary hypertension). Background technique [0007] Inhibition of TGF-β signaling has been attempted for the treatment of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K39/395A61P11/00A61P17/00A61P17/02A61P9/12
CPCC07K2319/30C07K2319/32A61K45/06A61K38/1841A61P11/00A61P17/00A61P17/02A61P9/12A61K39/3955C07K16/22C07K14/475C07K2317/76A61K2039/505C07K14/495C07K2319/74
Inventor 莱明·杨保尔·B·于
Owner THE BRIGHAM & WOMEN S HOSPITAL INC