Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
  • A01N1/10—Preservation of living parts
  • A01N1/14—Mechanical aspects of preservation; Apparatus or containers therefor
  • A01N1/142—Apparatus
  • A01N1/143—Apparatus for organ perfusion
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
  • A01N1/10—Preservation of living parts
  • A01N1/12—Chemical aspects of preservation
  • A01N1/122—Preservation or perfusion media
  • A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1891—Angiogenesic factors; Angiogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/193—Colony stimulating factors [CSF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/196—Thrombopoietin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
  • A61K38/2066—IL-10
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• This application describes an apparatus and a method for the treatment of a damaged lung, heart, or other organ or tissue using cells contained in the apparatus and a liquid interface that allows communication with the circulation of the damaged organ or tissue.
• the apparatus can be used to treat the organ inside or outside the body.
• the apparatus is designed to sit outside the body but a similar apparatus is envisioned that is implantable.
• the apparatus contains a porous material or matrix that the cells are grown on, and the volume of the apparatus provides that it can contain a therapeutically useful number of cells in the range 0.5 x 10e6 to 200 x 10e6.
• the cells are contained in the apparatus and a filter with 1 micron pores prevents cells from being transported to the organ or tissue.
• the apparatus is connected to the organ or tissue in a way that allows fluid flow from the organ or tissue to the apparatus and from the apparatus to the organ or tissue of interest. This may be the same organ/tissue or a different organ/tissue.
• the fluid flow may be re-circulated from the apparatus to the organ/tissue.
• the cells contained in the apparatus may produce growth factors, cytokines or other substances that are useful to inhibit inflammation, enhance tissue and organ recovery from injury or disease, and stimulate growth of new blood vessels and aid in forming new tissue.
• the cells in the apparatus can be modified to express additional therapeutic molecules.
• the cells in the apparatus can be immortalized cells that provide a consistent and continuous source of the cells that can be carefully evaluated and provide a reliable production of the desired growth factors, cytokines and other substances.
• the cells in the apparatus can respond to signals (molecules) from the injured or diseased organ or tissue and change their expression of cytokines growth factors and other substances.
• the cells in the apparatus can be immortalized cells and provide these growth factors and cytokines or the immortalized MSCs can be genetically modified to express additional factors of therapeutic value. Background
• Lung donor quality continues to be a major hurdle in lung transplantation, hampering the number of procedures performed every year; merely 15-20 % of available multi-organ donors become lung donors.
• donor quality is a significant determinant of recipient survival after transplantation.
• Several mechanisms define the quality of the donated lung, mostly related to the inflammatory response elicited by brain death, mechanical ventilation, gastric aspiration, trauma, and cold ischemic storage. These responses ultimately induce primary graft dysfunction and acute rejection, leading to a decrease in organ and patient survival by favoring chronic rejection.
• the lung's architecture presents a complex dilemma in terms of organ preservation and reconditioning.
• Cells in the endothelial and epithelial surfaces have been implicated with the production of molecular markers that regulate organ dysfunction and repair.
• the endothelium appears to be a predominant source of oxidants, upregulated adhesion molecules, prothrombotic and antifibrinolitic factors that lead to microvascular thrombosis compromising blood flow after reperfusion.
• brain death and prolonged cold ischemia favor the loss of the water- containing properties in the alveolar epithelium. This leads to the development of pulmonary edema, which compromises lung oxygen exchange and cellular viability.
• ex vivo perfusion system has been developed and has the ability to maintain lungs outside the body for many hours.
• This system that does not require the use of blood or blood components has a proprietary buffered acellular solution, with plasma-like osmotic and oncotic pressures, and maintains the lungs for extended periods of time outside the body without adversely impacting their physiology.
• a apparatus containing stem cells could provide important growth factors and cytokines during ex vivo lung perfusion to maintain or improve the lung health ex vivo.
• This apparatus and procedure could become an important therapeutic option for organ reconditioning before transplantation, ultimately improving the quality of the lung to be transplanted, and increasing the number of usable lungs and transplant survival.
• the Ex-vivo Cellular Therapy apparatus can be used to treat lungs ex- vivo.
• the cells in the apparatus produce growth factors and cytokines that can enhance tissue repair in the lung. It can also be used to treat the lungs in situ as may be needed to treat infection or idiopathic lung disease.
• the cells in the XCT-apparatus can respond to signals from damaged tissue to produce different growth factors and cytokines that enhance tissue repair.
• a related implantable in vivo cellular therapy apparatus is envisioned.
• the apparatus will be connected in-line with the ex vivo perfusion system and receive the fluid from the pulmonary vein.
• the cells in the apparatus will be perfused by the post-lung fluid.
• This will bring into the apparatus a representative molecular sample of the lung's inflammatory status triggering an adaptive response from the cells in the apparatus such that the cells alter their "paracrine secretome" that is, the molecules secreted from the cells including beneficial factors (including molecules that are growth factors and cytokines).
• beneficial factors including molecules that are growth factors and cytokines.
• MSCs Several factors produced by MSCs could be involved in the resuscitation of these injured organs. Some of these factors secreted by MSCs that could down -regulate inflammation and modulate endothelial/epithelial dysfunction are:
• Interleukin 1 receptor antagonist IL-lra
• Interleukin-1 pathway plays an important role in the generation of sterile inflammation similarly to the effects of tumor necrosis factor alpha (TNFalpha) in infectious inflammation.
• IL-lra secreted by MSCs blunts the effects of IL-1 and TNFalpha attenuating inflammation by reprograming macrophages from the pro-inflammatory type (Ml) to the anti-inflammatory phenotype (M2).
• Ml pro-inflammatory type
• M2 anti-inflammatory phenotype
• Other cytokines secreted by MSCs -IL-10, TNFalpha stimulated gene/protein 6 (TSG-6) and PGE2 may contribute to down-regulate inflammation by a similar mechanism, ultimately decreasing the amplification of pro-inflammatory signals by the lung cells.
• TSG-6 TNFalpha stimulated gene/protein 6
• PGE2 may contribute to down-regulate inflammation by a similar mechanism, ultimately decreasing the amplification of pro-inflammatory signals by the
• Angl 2- Angiopoietin- 1
• Angl is a growth factor that stabilizes the endothelium, reduces its permeability and inhibits leukocyte-endothelium interactions by modifying endothelial cell adhesion molecules and cell junctions. Additionally, it has been reported to reduce protein permeability in alveolar epithelial type II cell cultures.
• KGF Keratinocyte growth factor
• TGFbeta TGFbeta
• HGF HGF
• PGE2 Gal-1
• iNOS IL-6
• CD73 IL-lRag
• IL-10 HLA-G
• IDO TSG-6

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Zoology (AREA)
• Immunology (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Developmental Biology & Embryology (AREA)
• Cell Biology (AREA)
• Wood Science & Technology (AREA)
• Environmental Sciences (AREA)
• Dentistry (AREA)
• Virology (AREA)
• Hematology (AREA)
• Biomedical Technology (AREA)
• Biotechnology (AREA)
• Vascular Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pulmonology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• External Artificial Organs (AREA)
• Biophysics (AREA)
• Physiology (AREA)

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• 2013
  • 2013-10-15 US US14/435,629 patent/US20150296770A1/en not_active Abandoned
  • 2013-10-15 AU AU2013331412A patent/AU2013331412A1/en not_active Abandoned
  • 2013-10-15 JP JP2015537771A patent/JP2015536322A/ja active Pending
  • 2013-10-15 EP EP13847671.8A patent/EP2906232A4/en not_active Withdrawn
  • 2013-10-15 WO PCT/US2013/065033 patent/WO2014062669A1/en not_active Ceased

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