ES2546937T3 - Terapia génica basada en fibroblastos y células endoteliales para el sistema pulmonar - Google Patents
Terapia génica basada en fibroblastos y células endoteliales para el sistema pulmonar Download PDFInfo
- Publication number
- ES2546937T3 ES2546937T3 ES07009031.1T ES07009031T ES2546937T3 ES 2546937 T3 ES2546937 T3 ES 2546937T3 ES 07009031 T ES07009031 T ES 07009031T ES 2546937 T3 ES2546937 T3 ES 2546937T3
- Authority
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- cells
- fibroblasts
- endothelial cells
- gene therapy
- therapy based
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 210000002950 fibroblast Anatomy 0.000 title abstract description 6
- 230000002685 pulmonary effect Effects 0.000 title description 2
- 210000002889 endothelial cell Anatomy 0.000 title 1
- 238000001415 gene therapy Methods 0.000 title 1
- 210000004027 cell Anatomy 0.000 abstract description 20
- 230000002500 effect on skin Effects 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- 238000012546 transfer Methods 0.000 abstract description 3
- 210000000056 organ Anatomy 0.000 abstract description 2
- 208000002815 pulmonary hypertension Diseases 0.000 abstract description 2
- 108700019146 Transgenes Proteins 0.000 abstract 2
- 239000002870 angiogenesis inducing agent Substances 0.000 abstract 2
- 230000004087 circulation Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 230000004088 pulmonary circulation Effects 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 210000004072 lung Anatomy 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 4
- OPIFSICVWOWJMJ-AEOCFKNESA-N 5-bromo-4-chloro-3-indolyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CNC2=CC=C(Br)C(Cl)=C12 OPIFSICVWOWJMJ-AEOCFKNESA-N 0.000 description 3
- 102000005936 beta-Galactosidase Human genes 0.000 description 3
- 108010005774 beta-Galactosidase Proteins 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 102000058223 human VEGFA Human genes 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- QVCMHGGNRFRMAD-UHFFFAOYSA-N monocrotaline Natural products C1OC(=O)C(C)(O)C(O)(C)C(C)C(=O)OC2CCN3C2C1=CC3 QVCMHGGNRFRMAD-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- -1 potassium ferricyanide Chemical compound 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- IDBGJRAMJYRSKU-UHFFFAOYSA-N cropodine Natural products CC1C(=O)OC2CCN3CCC(COC(=O)C(C)(O)C1(C)O)C23 IDBGJRAMJYRSKU-UHFFFAOYSA-N 0.000 description 1
- QPNKYNYIKKVVQB-UHFFFAOYSA-N crotaleschenine Natural products O1C(=O)C(C)C(C)C(C)(O)C(=O)OCC2=CCN3C2C1CC3 QPNKYNYIKKVVQB-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 210000005119 human aortic smooth muscle cell Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- QVCMHGGNRFRMAD-XFGHUUIASA-N monocrotaline Chemical compound C1OC(=O)[C@](C)(O)[C@@](O)(C)[C@@H](C)C(=O)O[C@@H]2CCN3[C@@H]2C1=CC3 QVCMHGGNRFRMAD-XFGHUUIASA-N 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000011426 transformation method Methods 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
Classifications
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- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
-
- 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
- A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal 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
- A61K38/1858—Platelet-derived growth factor [PDGF]
- A61K38/1866—Vascular endothelial growth factor [VEGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
- C12Y114/13—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with NADH or NADPH as one donor, and incorporation of one atom of oxygen (1.14.13)
- C12Y114/13039—Nitric-oxide synthase (NADPH dependent) (1.14.13.39)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Engineering & Computer Science (AREA)
- Toxicology (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Pulmonology (AREA)
- Wood Science & Technology (AREA)
- Vascular Medicine (AREA)
- Biophysics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Uso de células de mamífero transfectadas, viables, seleccionadas de fibroblastos y células endoteliales, conteniendo dichas células de mamífero transfectadas al menos un transgen expresable que codifica un factor angiogénico o vasoactivo para la preparación de una composición farmacéutica para aliviar un trastorno pulmonar en un paciente o síntomas del mismo, en donde dicha composición farmacéutica se ha de administrar a la circulación pulmonar de un paciente mamífero.
Description
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E07009031
09-09-2015
cm/2 u 85% del valor de 30 minutos, lo que indica una excelente supervivencia de las células trasplantadas. También se evalúa la supervivencia de células marcadas con CMTMR en instantes posteriores de 2, 4, 7 y 14 días y 1, 2, 3 y 6 meses para establecer el transcurso del tiempo de supervivencia de células trasplantadas en los pulmones de ratas receptoras. No se observaron señales brillantemente fluorescentes en ninguno de los pulmones a los que se inyectaron células de la musculatura lisa no marcadas.
En el tejido del bazo, hígado y músculo esquelético no se identificaron señales fluorescentes. En 2 de 4 riñones examinados, podían identificarse señales fluorescentes irregulares. Ninguna de éstas parecía ajustarse a la forma de una célula entera, y se presumió que representan a las células que fueron cortadas o destruidas durante la inyección de células o poco después. Además, no se identificaron señales fluorescentes en órgano alguno fuera del pulmón 7 días después de la inyección.
EJEMPLO 5 -DETECCIÓN DE EXPRESIÓN DE BETA-GALACTOSIDASA EN TEJIDO
En varios instantes después de la transferencia génica basada en células, se sacrificó a los animales y se les abrió el pecho. La arteria pulmonar se lava con solución salina y la tráquea se canula y se lava con 2% de paraformaldehído hasta que los pulmones están bien inflados. Se toman cortes transversales de los segmentos basal, medio y apical de los dos pulmones, y se obtienen muestras del hígado, bazo, riñón y músculo gastrocnemio de determinados animales. Las muestras se incuban en 2% de paraformaldehído con 0,2% de glutaraldehído durante 1 hora, y luego se enjuagan en PBS. El tejido se incuba a continuación durante 18 horas a 37ºC con una disolución de cromógeno que contiene 0,2% de 5-bromo-4-cloro-3-indolil-β-D-galactósido (X-Gal, Boehringer Mannheim, Laval, Quebec), ferrocianuro de potasio 5 milimolar (Sigma), ferricianuro de potasio 5 milimolar (Sigma) y cloruro de magnesio 2 milimolar (Sigma), todos disueltos en solución salina tamponada con fosfato. Las muestras se enjuagan luego en PBS, se embeben en compuesto OCT (Miles Laboratories), se cortan en secciones de 10 micras y se tiñen para contraste con rojo neutro.
Luego se examinan al microscopio secciones vistas, y se pueden estimar el número de células que se tiñen intensamente de azul. Dado que se utiliza una placa de células para la tinción in vitro para determinar la eficiencia de la transfección para cada una de las series de reacción, se puede hacer para cada animal una estimación del porcentaje de células que fueron transfectadas con el plásmido de gen informador pCMV-βGal. Utilizando esta información y el cálculo matemático descrito para aproximar el número de células T fluorescentes presentes, puede hacerse una estimación del número total de células transfectadas restantes en el momento del sacrificio de los animales.
En un cierto número de reacciones de transfección separadas utilizando el plásmido pCMV-βGal, se puede obtener una eficiencia media de la transfección del orden de 40 -50% con los fibroblastos dérmicos in vitro. No se observa tinción alguna en cultivos transfectados simulados.
Tras la incubación con la disolución de cromógeno X-Gal, se puede observar una evidencia microscópica de la expresión transgénica basada en células a las 48 horas después de la inyección de células fibroblastos dérmicos transfectadas con pCMV-βGal en la vena yugular interna, observándose múltiples células que se tiñen de azul intenso a lo largo del pulmón, lo que representa al menos el 30% de las células transfectadas originales que fueron inyectadas. Al igual que con las células marcadas por fluorescencia, la mayoría de las células que expresan betagalactosidasa parecen estar alojadas dentro de la microvasculatura distal del pulmón. No se detecta evidencia de expresión alguna de beta-galactosidasa en cualquiera de los pulmones de los animales a los que se inyectaron células de fibroblastos dérmicos no transfectadas. No se observa evidencia alguna de patología pulmonar, tal como se determina por la presencia de un infilitrado polimorfonuclear anormal o linfocítico, engrosamiento septal o destrucción alveolar.
EJEMPLO 6 -ESTUDIOS DE PREVENCIÓN DE MONOCROTALINA
Para determinar si la transferencia génica basada en células de VEGF165 sería capaz de inhibir el desarrollo de la hipertensión pulmonar en un modelo animal de la enfermedad, se prepararon como se describe anteriormente fibroblastos dérmicos que habían sido transfectados con pVEGF o pcDNA 3.1 (un vector vacío). La secuencia codificadora de longitud completa de VEGF165 se generó realizando una reacción en cadena de la polimerasa de transcripción inversa utilizando ARN total extraído de células de la musculatura lisa aórtica humana y los siguientes cebadores específicos para la secuencia siguiente: sentido 5' TCGGGCCTCCGAAACCATGA 3', antisentido 5' CCTGGTGAGAGATCTGGTTC 3'. Esto generó un fragmento de 649 pb que se clonó en el vector pGEM-T (Promega, Madison, Wisconsin) y se secuenció para confirmar la identidad. El fragmento fue clonado después en el vector de expresión pcDNA 3.1 en el sitio de restricción EcoR1, y la orientación correcta se determinó utilizando un digesto diferencial. El vector deficiente en inserto (pcDNA 3.1) se utilizó como un control para los experimentos de monocrotalina. Todo el ADN del plásmido se introdujo en una cepa JM 109 de E. coli a través del método de transformación por choque térmico, y las bacterias se cultivaron durante la noche en medio LB que contenía 100 microgramos/mililitro de ampicilina. El plásmido se purificó después utilizando un kit de purificación libre de
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Claims (1)
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imagen1
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CA1999/000869 WO2001021184A1 (en) | 1999-09-23 | 1999-09-23 | Cell-based gene therapy for the pulmonary system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2546937T3 true ES2546937T3 (es) | 2015-09-30 |
Family
ID=4173386
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES07009031.1T Expired - Lifetime ES2546937T3 (es) | 1999-09-23 | 1999-09-23 | Terapia génica basada en fibroblastos y células endoteliales para el sistema pulmonar |
Country Status (11)
| Country | Link |
|---|---|
| EP (2) | EP1839667B1 (es) |
| JP (1) | JP2003509463A (es) |
| AT (1) | ATE364387T1 (es) |
| AU (1) | AU5724499A (es) |
| BR (1) | BR9917500A (es) |
| CA (1) | CA2383093A1 (es) |
| DE (1) | DE69936320T2 (es) |
| ES (1) | ES2546937T3 (es) |
| IL (3) | IL148826A0 (es) |
| MX (1) | MXPA02003131A (es) |
| WO (1) | WO2001021184A1 (es) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2020240049A1 (en) | 2019-03-19 | 2021-11-04 | Figene, Llc | Treatment of chronic obstructive pulmonary disease and lung degeneration using activated fibroblasts and exosome derivatives thereof |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5219740A (en) * | 1987-02-13 | 1993-06-15 | Fred Hutchinson Cancer Research Center | Retroviral gene transfer into diploid fibroblasts for gene therapy |
| EP0456640A1 (en) * | 1988-12-13 | 1991-11-21 | UNITED STATES GOVERNMENT as represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES | Genetically engineered endothelial cells and use thereof |
| US5240846A (en) * | 1989-08-22 | 1993-08-31 | The Regents Of The University Of Michigan | Gene therapy vector for cystic fibrosis |
| WO1992015676A1 (en) * | 1991-03-08 | 1992-09-17 | The Salk Institute For Biological Studies | Somatic cell gene therapy |
| AU3429993A (en) * | 1992-01-10 | 1993-08-03 | Georgetown University | A method of administering genetically engineered endothelial cells to sites of angiogenesis for effecting genetic therapy |
| CA2086844A1 (en) * | 1993-01-07 | 1994-07-08 | Ian D. Dube | Method and product of gene transfer into cells |
| CA2260771A1 (en) * | 1996-07-17 | 1998-01-22 | The General Hospital Corporation | Method of inducing vasodilation and treating pulmonary hypertension using adenoviral-mediated transfer of the nitric oxide synthase gene |
| KR100695590B1 (ko) * | 1996-11-01 | 2007-03-14 | 아크 테라퓨틱스 리미티드 | 산화질소 또는 프로스타시클린 생산을 자극하는 약제의 치료학적 용도 및 전달 기구 |
| US5980887A (en) * | 1996-11-08 | 1999-11-09 | St. Elizabeth's Medical Center Of Boston | Methods for enhancing angiogenesis with endothelial progenitor cells |
| EP0893493A3 (de) * | 1997-07-21 | 2002-12-04 | Aventis Pharma Deutschland GmbH | Genetisch veränderte Zellen und deren Verwendung in der Prophylaxe oder Therapie von Erkrankungen |
| US6147109A (en) * | 1997-10-14 | 2000-11-14 | The General Hospital Corporation | Upregulation of Type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors |
| SG117417A1 (en) * | 1998-02-06 | 2005-12-29 | Collateral Therpeutics Inc | Variants of the angiogenic factor vascular endothelial cell growth factor: vegf |
| CA2227425A1 (en) * | 1998-03-27 | 1999-09-27 | An-Go-Gen Inc. | Cell-based gene therapy |
| CA2266805C (en) * | 1998-03-27 | 2015-04-28 | An-Go-Gen Inc. | Cell-based gene therapy in the treatment of pulmonary disorders |
-
1999
- 1999-09-23 BR BR9917500-2A patent/BR9917500A/pt not_active IP Right Cessation
- 1999-09-23 MX MXPA02003131A patent/MXPA02003131A/es active IP Right Grant
- 1999-09-23 AT AT99944205T patent/ATE364387T1/de active
- 1999-09-23 JP JP2001524610A patent/JP2003509463A/ja active Pending
- 1999-09-23 AU AU57244/99A patent/AU5724499A/en not_active Abandoned
- 1999-09-23 EP EP07009031.1A patent/EP1839667B1/en not_active Expired - Lifetime
- 1999-09-23 ES ES07009031.1T patent/ES2546937T3/es not_active Expired - Lifetime
- 1999-09-23 IL IL14882699A patent/IL148826A0/xx unknown
- 1999-09-23 CA CA 2383093 patent/CA2383093A1/en not_active Abandoned
- 1999-09-23 DE DE1999636320 patent/DE69936320T2/de not_active Expired - Lifetime
- 1999-09-23 EP EP99944205A patent/EP1220679B1/en not_active Expired - Lifetime
- 1999-09-23 WO PCT/CA1999/000869 patent/WO2001021184A1/en not_active Ceased
-
2002
- 2002-03-21 IL IL14882602A patent/IL148826A/en not_active IP Right Cessation
-
2008
- 2008-07-17 IL IL192893A patent/IL192893A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1839667A3 (en) | 2010-04-14 |
| EP1220679B1 (en) | 2007-06-13 |
| JP2003509463A (ja) | 2003-03-11 |
| IL148826A0 (en) | 2002-09-12 |
| EP1220679A1 (en) | 2002-07-10 |
| IL148826A (en) | 2010-12-30 |
| CA2383093A1 (en) | 2001-03-29 |
| DE69936320T2 (de) | 2008-02-21 |
| DE69936320D1 (de) | 2007-07-26 |
| EP1839667A2 (en) | 2007-10-03 |
| IL192893A0 (en) | 2009-02-11 |
| MXPA02003131A (es) | 2003-08-20 |
| BR9917500A (pt) | 2002-05-21 |
| EP1839667B1 (en) | 2015-06-17 |
| ATE364387T1 (de) | 2007-07-15 |
| WO2001021184A1 (en) | 2001-03-29 |
| AU5724499A (en) | 2001-04-24 |
| IL192893A (en) | 2014-03-31 |
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