Methods for increasing the selective efficacy of gene therapy using CAR peptide and heparan-sulfate mediated macropinocytosis
Inventors
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Vascular BioSciencesVascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Vascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Publication Number
US-9603890-B2
Publication Date
2017-03-28
Expiration Date
Abstract
Disclosed are compositions and methods for triggering disease selective macropinocytosis. The compositions can serve as a marker of disease activity and as a trigger of enhanced macropinocytosis in tissues undergoing disease remodeling such as wound healing, cancer, PAH, inflammation, diabetes, Crohn's disease, ulcerative colitis, ankylosing spondylitis, diseases of the endometrium, psoriasis, irritable bowel syndrome, arthritis, fibrotic disorders, interstitial cystitis, autoimmune diseases, asthma, acute lung injury, and adult respiratory distress syndrome. The compositions can also serve as a receptor for disease selective cell penetrating peptides in the cells and extracellular matrix of diseased tissues.
Core Innovation
The invention relates to CAR (CARSKNKDC) peptides and truncated CAR (tCAR) peptides that target a heparan sulfate moiety, IdoA2S-GlcNS. Binding to the heparan sulfate moiety triggers heparan sulfate-mediated, lipid-raft macropinocytosis in diseased, remodeled tissues, linking increased macropinocytosis to disease-selective uptake in the affected tissue.
Increased macropinocytosis is used to enhance the localization and effect of co-administered therapeutics. The disclosed example includes co-administration of CAR with enhanced adenoviral MFN2 gene therapy in a severe occlusive PAH rat model, and increased MFN2 gene expression is described as a notable outcome of CAR co-administration.
The document further frames diagnostic and therapeutic uses that involve heparan sulfate-related markers and enzymes. It proposes related diagnostic and therapeutic uses for disease markers such as heparanase (HPSE), heparinase I, HS2ST1, and HS6ST3 across multiple disease indications.
Claims Coverage
The partial content includes one independent claim. The independent claim describes a method with four inventive features that together: select an individual based on increased heparan sulfate moiety levels, administer a CAR/tCAR peptide that targets IdoA2S-GlcNS, co-administer a PAH drug, and increase the rate of macropinocytosis in target cells.
Screening for increased heparan sulfate moiety levels
Screening an individual for increased levels of a heparin sulfate moiety selected from the group consisting of 2-O-sulfo-α-L-iduronic acid-2-deoxy-2-acetamido-α-D-glucopyranosyl, IdoA2S-GlcNS, heparinase I, and heparanase (HPSE).
Disease identification for pulmonary hypertension (PAH)
Identifying the presence of a disease requiring treatment according to the increased levels of the compound detected wherein the disease is pulmonary hypertension (PAH).
Administering an IdoA2S-GlcNS-targeting peptide for selective penetration
Administering to said individual a peptide that targets the receptor IdoA2S-GlcNS and selectively penetrates the cells and extracellular matrix of diseased tissues wherein the peptide is selected from the group consisting of CAR (SEQ ID NO: 1) and tCAR (SEQ ID NO: 2).
Co-administering a PAH drug with CAR/tCAR and increasing macropinocytosis
Co-administering to said individual a drug for treatment of PAH with said peptide and increasing the rate of macropinocytosis in the target cells.
Across the independent claim, the core inventive concept is to identify individuals with pulmonary hypertension associated with increased heparan sulfate moiety levels, administer a peptide targeting IdoA2S-GlcNS (CAR or tCAR) that selectively penetrates diseased cells and extracellular matrix, co-administer a PAH treatment drug with the peptide, and increase the rate of macropinocytosis in target cells.
Stated Advantages
Increasing the concentration of co-administered drugs in an individual.
Increasing the rate of macropinocytosis in target cells.
Enabling selective penetration of diseased cells and extracellular matrix of diseased tissues (as recited for the peptide).
Documented Applications
Treatment of pulmonary hypertension (PAH) using a co-administered PAH drug with a peptide selected from CAR (SEQ ID NO: 1) and tCAR (SEQ ID NO: 2).
Enhancing adenoviral MFN2 gene therapy efficacy via CAR co-administration in a severe occlusive PAH rat model, with increased MFN2 gene expression described as a notable outcome.
Diagnostic and therapeutic uses involving disease markers including heparanase (HPSE), heparinase I, HS2ST1, and HS6ST3 across multiple disease indications.
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