Treating inflammatory lung disease
Inventors
Jackson, Robert M. • Schally, Andrew V. • Cai, Renzhi
Assignees
US Department of Veterans Affairs
Publication Number
US-11993640-B2
Publication Date
2024-05-28
Expiration Date
2040-02-08
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Abstract
Described herein are compositions and methods for treating pulmonary fibrosis and cancer. The compositions include growth hormone releasing hormone peptides. The methods include reducing lung inflammation, lung scarring, reducing expression of T cell receptor complex genes as well as inhibiting tumor growth.
Core Innovation
Described herein are compositions and methods involving growth hormone releasing hormone (GHRH) receptor antagonists, particularly peptides, for treating pulmonary fibrosis and cancer. The methods include reducing lung inflammation, reducing lung scarring, ameliorating symptoms of pulmonary fibrosis, reducing expression of T cell receptor complex genes, and inhibiting tumor growth. The compositions encompass peptides of formula I and II with specific amino acid substitutions as detailed in the description, including various AVR peptides and their variants.
The background identifies idiopathic pulmonary fibrosis (IPF) as a fibrosing interstitial lung disease characterized by lung inflammation and scarring with poor prognosis, related to genetic and environmental factors. It also discusses the role of GHRH and its receptors, including splice variant receptors found in peripheral tissues and many cancers and in lung tissue. GHRH acts as an autocrine/paracrine growth factor promoting cell proliferation, fibrosis and tumor growth via GH and IGF-1 signaling pathways. There is a lack of effective treatments that modulate these pathways to reduce fibrosis and tumor proliferation.
The innovation solves the problem of pulmonary fibrosis and tumor growth by employing GHRH receptor antagonists that inhibit GHRH signaling. These peptides reduce lung inflammation, fibrosis, and scarring, decrease expression of genes involved in T cell receptor signaling, and inhibit tumor growth across multiple cancer models. The methods and compositions provide therapeutic means to treat pulmonary fibrosis and cancer by blocking growth hormone releasing hormone activity and associated downstream pathological processes.
Claims Coverage
The patent includes three independent claims focusing on methods of treating pulmonary fibrosis by administering specific growth hormone releasing hormone (GHRH) receptor antagonist peptides.
Method of reducing lung inflammation with a specific GHRH receptor antagonist peptide
Administering to a subject with pulmonary fibrosis a therapeutically effective amount of a GHRH receptor antagonist peptide having the amino acid sequence PhAC-Ada-Tyr D-Arg Asp Ala Ile 5FPhe Thr Ala Har Tyr(Me) His Orn Val Leu Abu Gln Leu Ser Ala His Orn Leu Leu Gln Asp Ile Nle D-Arg Har-NH2.
Method of reducing lung scarring with a specific GHRH antagonist peptide
Administering to a subject with pulmonary fibrosis a therapeutically effective amount of a GHRH antagonist peptide comprising the amino acid sequence PhAC-Ada-Tyr D-Arg Asp Ala Ile 5FPhe Thr Ala Har Tyr(Me) His Orn Val Leu Abu Gln Leu Ser Ala His Orn Leu Leu Gln Asp Ile Nle D-Arg Har-NH2.
Method of ameliorating symptoms of pulmonary fibrosis with a specific GHRH antagonist peptide
Administering to a subject with pulmonary fibrosis a therapeutically effective amount of a GHRH antagonist peptide comprising the amino acid sequence PhAC-Ada-Tyr D-Arg Asp Ala Ile 5FPhe Thr Ala Har Tyr(Me) His Orn Val Leu Abu Gln Leu Ser Ala His Orn Leu Leu Gln Asp Ile Nle D-Arg Har-NH2, wherein the symptoms include breathlessness, cough, decreased exercise tolerance, hypoxemia, or a combination thereof.
The claims cover methods of treating pulmonary fibrosis by administering defined GHRH receptor antagonist peptides that reduce lung inflammation, scarring, and symptoms, specifically through peptides comprising a defined amino acid sequence.
Stated Advantages
GHRH receptor antagonists reduce lung inflammation caused by bleomycin-induced injury.
They decrease lung fibrosis and scarring as shown by histopathological and biochemical markers.
These antagonists downregulate genes related to T cell activation and immune response, modulating the cellular immune response.
They inhibit tumor growth in multiple cancer models, including pancreatic, lung, stomach, breast, ovarian, and prostate cancers.
Certain GHRH antagonists show higher inhibitory potency against tumor cell proliferation compared to reference compounds.
GHRH antagonists increase basal and maximal oxygen consumption in lung fibroblasts, indicating modulation of mitochondrial function.
Documented Applications
Treatment of pulmonary fibrosis by administering GHRH receptor antagonists to reduce lung inflammation and scarring and ameliorate symptoms.
Use in inhibiting tumor growth across various cancers including pancreatic, lung, stomach, breast, ovarian, colorectal, and prostate cancers.
Reduction of T cell receptor complex gene expression in pulmonary fibrosis patients.
Combination therapy with androgen deprivation, chemotherapeutic agents, radiotherapy, immunotherapy, apoptosis regulators, surgery, or other agents in cancer treatment.
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