Use of ASC and ASC-CM to treat ARDS, SARS, and MERS
Inventors
March, Keith • Bogatcheva, Natalia
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-10143709-B2
Publication Date
2018-12-04
Expiration Date
2035-05-06
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Abstract
Disclosed herein is that the systemic administration of ASC conditioned media diminished LPS-induced lung injury by inhibiting epithelial permeability, neutrophil inflammatory response, and secretion of pro-inflammatory TNFα. It is also shown that ARDS lung is able to retain IV-delivered ASC for a substantial amount of time, with no evidence of the significant cell distribution to other organs at this time point. These findings provide optimization of cell-based and cell-free therapy for the treatment of ARDS, including occurrences of ARDS caused by upper respiratory tract infections such as SARS and MERS.
Core Innovation
The invention relates to the systemic administration of adipose-derived Adult Stem Cell Conditioned Media (ASC-CM) and adult stem cells (ASC) to treat Adult Respiratory Distress Syndrome (ARDS), including ARDS caused by upper respiratory tract infections such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The therapy diminishes lung injury by inhibiting epithelial permeability, neutrophil inflammatory response, and secretion of pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNFα). The findings additionally show that ARDS-affected lungs retain intravenously delivered ASC for a substantial duration without significant distribution to other organs at the same time point.
ARDS is a severe pathological condition leading to pulmonary failure and requiring intensive care treatment. It can be triggered by various pulmonary and non-pulmonary causes, including pneumonia, aspiration, sepsis, trauma, and is a proximal cause of morbidity in diseases caused by coronaviruses SARS-CoV and MERS-CoV. Current treatments are primarily supportive and pharmacological or non-pharmacological strategies targeting components of the disease mechanism have failed to improve mortality over more than 20 years.
The invention addresses the problem of the lack of effective therapies for ARDS by proposing a novel complex therapy using ASC or ASC-CM. ASC-CM and ASC have demonstrated suppression of lung histopathological changes, reduction of neutrophil infiltration, and decrease in lung permeability and pro-inflammatory cytokine release in a murine model of LPS-induced ARDS. The therapy also strengthens endothelial barrier function and suppresses inflammation and barrier hyperpermeability which are key mechanisms contributing to lung edema development in ARDS.
Claims Coverage
The patent contains one independent method claim covering the treatment with adipose-derived Adult Stem Cell-Conditioned Media (ASC-CM). The main inventive features focus on the use of ASC-CM derived from ASC lacking CD31 and CD45 markers to treat ARDS caused by inflammation and barrier hyperpermeability in human or animal patients.
Use of adipose-derived Adult Stem Cell-Conditioned Media to treat ARDS
Administering at least one therapeutically effective dose of adipose-derived ASC-CM derived from ASC negative for CD31 and CD45 to a patient afflicted with Adult Respiratory Distress Syndrome caused by inflammation and barrier hyperpermeability, wherein the patient is human or animal.
Treatment of ARDS caused by coronavirus infections
Administration of adipose-derived ASC-CM for treatment where ARDS is caused by upper respiratory tract infections from coronaviruses SARS-CoV and MERS-CoV.
Intravenous administration of therapeutically effective doses
Delivering the ASC-CM intravenously, including specific doses expressed as 0.1 ml/kg to 2.0 ml/kg or 0.5 ml/kg to 1.0 ml/kg of 100× concentration.
Use of ASC-CM comprising material above defined molecular weights
Use of ASC-CM comprising material having molecular weights greater than defined thresholds, e.g., above about 10,000 Daltons up to 150,000 Daltons, optionally formulated to avoid heat or exosome sensitivity.
Use of ASC-CM fractions comprised of exosomes
Administration of therapeutically effective doses of ASC-CM fractions comprised of exosomes, concentrated by filtration, centrifugation, or precipitation and resuspension, via intravenous or lung aspiration routes.
Suppression of inflammation and barrier hyperpermeability
Method of suppressing inflammation and barrier hyperpermeability by providing therapeutically effective doses of adipose-derived ASC-CM derived from ASC negative for CD31 and CD45, applicable to humans, animals, cells, or tissues.
The independent claim covers methods of treating ARDS in humans or animals by administering adipose-derived ASC-CM derived from ASC negative for CD31 and CD45, with inventive features including the molecular weight ranges of ASC-CM components, delivery routes (intravenous and lung aspiration), use of exosome fractions, dosage forms, and applications to ARDS caused by coronaviruses.
Stated Advantages
Avoidance of stem cell isolation procedures by using ASC-CM as an off-the-shelf therapeutic product, facilitating treatment of critically ill patients.
ASC-CM avoids concerns associated with stem cell homing to pre-existing tumors, providing a safer cell-free therapeutic option.
Reduction of lung inflammatory histological changes, protein extravasation, pro-inflammatory cytokine secretion, and neutrophil oxidative damage in ARDS treatment.
Enhancement of endothelial barrier function and suppression of inflammation and barrier hyperpermeability, key pathological mechanisms of ARDS.
Sustained retention of intravenously delivered ASC in ARDS lungs supports less frequent dosing requirements for stem cell therapy efficacy.
Documented Applications
Treatment of Adult Respiratory Distress Syndrome (ARDS) in humans and animals.
Treatment of ARDS caused by upper respiratory tract infections with coronavirus SARS-CoV and MERS-CoV.
Suppression of lung inflammation and barrier hyperpermeability induced by gram-negative bacterial infection or endotoxin.
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