EP1903872A2 - Prevention of chronic rejection in solid organ transplantation - Google Patents

Prevention of chronic rejection in solid organ transplantation

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Publication number
EP1903872A2
EP1903872A2 EP06774461A EP06774461A EP1903872A2 EP 1903872 A2 EP1903872 A2 EP 1903872A2 EP 06774461 A EP06774461 A EP 06774461A EP 06774461 A EP06774461 A EP 06774461A EP 1903872 A2 EP1903872 A2 EP 1903872A2
Authority
EP
European Patent Office
Prior art keywords
solid organ
organ
rejection
transplantation
expression
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.)
Withdrawn
Application number
EP06774461A
Other languages
German (de)
French (fr)
Inventor
Haiyan Jiang
Glenn Pierce
M. Yuichi Nwaki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genzyme Corp
Original Assignee
Genzyme Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Genzyme Corp filed Critical Genzyme Corp
Publication of EP1903872A2 publication Critical patent/EP1903872A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention is in the field of solid organ transplantation, and specifically more efficient methods of preventing immune-mediated rejection of said transplanted organs.
  • Acute graft rejection refers to the immune response immediately following transplantation
  • chronic rejection refers to the longer term rejection that is marked by alloreactive antibody formation, leukocyte infiltration and accelerated graft ateriopathy as seen in heart transplant.
  • systemic general immune suppression can be used to prevent organ rejection, such generalized immune suppression exposes the subject to opportunistic infections, cancers (e.g.
  • IL-10 is an immunosuppressive modulator that plays important roles in peripheral T-cell tolerance.
  • IL-10 has been shown to skew the cytokine production from ThI to Th2 which is associated with long-survived grafts.
  • Thl-differentiating cytokine IL- 12 By inhibiting synthesis of Thl-differentiating cytokine IL- 12, IL-10 blocks Tl development, production of cytokines INF- ⁇ and IL-2, and therefore prevents potential graft destruction by CTL responses.
  • IL-10 has also been shown to promote apoptosis of alloreactive T cells via the Fas/FasL pathway, which is one of the mechanisms for graft survival.
  • IL-10 down regulates expression of MHC Class II and co- stimulatory molecules CD40, CD80 and CD86 on APC. Consequently, repetitive stimulation of T cells with alloantigens in the presence of IL-10 induces regulatory T cells producing IL- 10 and TGF- ⁇ with suppressive activities and results in prevention of graft rejection.
  • the present invention relates to the use of recombinant adeno- associated virus (rAAV) vectors to transducer cells of a solid organ to be transplanted with a nucleic acid sequence encoding an immunomodulatory polypeptide, e.g. IL-10, the expression of which reduces the likelihood of rejection of the transplanted organ by the host immune system.
  • rAAV adeno- associated virus
  • the invention further comprises the use of immunomodulatory agents to suppress acute rejection.
  • an immunosuppressive agent is administered at approximately the time of the transplant.
  • an immunosuppressive agent is administered prior to the transplant.
  • immunosuppressive agent(s) are one or more agents selected from the group including, but not limited to, IL-10 and FK506.
  • treatment with immunomodulatory agent(s) is curtailed or discontinued once rAAV-directed expression of the immunomodulatory polypeptide, e.g. IL-10, has begun.
  • the present invention relates to methods of improving the efficiency of solid organ transplantation by administering rAAV vectors encoding IL-10 to an isolated solid organ prior to transplantation of that organ into a subject.
  • IL-10 is expressed in at least some of the cells of the isolated organ after administration of the rAAV vectors.
  • the expression of IL-10 causes a shift from a Thl-like to a Th2-like immune response.
  • the solid organ to be transduced is the heart, kidney, liver, pancreatic islet, lung and intestine.
  • the present invention is related to the treatment of an isolated solid organ with an rAAV vector encoding an immunomodulatory polypeptide, e.g. IL-10, prior to transplantation of that organ into a subject.
  • an immunomodulatory polypeptide e.g. IL-10
  • the nucleic acid sequence encoding the immunomodulatory polypeptide is referred to herein as a transgene. Expression of the transgene within the cells and tissues of that transplanted organ may delay or/and prevent graft rejection.
  • Suitable immunomodulatory polypeptides that may be used in the methods of the present invention include, but are not limited to IL-10, IL-I inhibitors, CD-40 ligand inhibitors, TGF- ⁇ , GITR and FOXP3.
  • immunomodulatory agent refers to any immunomodulatory substance that is not delivered as a transgene by gene therapy, e.g. a small molecule, peptide or protein.
  • Immunomodulatory agents include, but are not limited to, IL-10 protein, FK506, cyclosporin, rapamycin, azathioprine, mycophenolate mofetil, cyclophosphamide, leflunomide, and corticosteroids.
  • a single immunomodulatory agent may be used, or two or more immunomodulatory agents may be used in combination, either sequentially or concurrently.
  • Anterograde/isolated heart or kidney is perfused with IxIO 12 vg vector for 20 minutes in the cold.
  • Biodistribution is determined by PCR and RT-PCR of rlL- 10 in various tissues including heart, lung, liver, kidney, spleen and PBMC.
  • the duration of graft survival is determined.
  • the expression of ThI cytokines are monokines is measured to determine whether they are down-regulated in AAV2-rIL10-transduced grafts.
  • a cytokine protein chip may be used if necessary to screen for a wider spectrum of cytokines regulated by IL' 10.
  • the levels of allore active antibodies and leukocyte infiltration are determined, as is the responsiveness of allospecific T cells.
  • Verwaerde C. et al Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA44'lg inhibits experimental autoimmune uveoretinities Gene Therapy 10 : 1970- 1981, 2003

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Transplantation (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of recombinant adenoassociated virus (rAAV) vectors to transduce cells of a solid organ to be transplanted with a nucleic acid sequence encoding an immunomodulatory polypeptide, e.g. IL-IO, the expression of which reduces the likelihood of rejection of the transplanted organ by the host immune system. Methods of improving the efficiency of solid organ transplantation by administering rAAV vectors encoding IL-IO to an isolated solid organ prior to transplantation of that organ into a subject are also described. The solid organ to be transduced may be the heart, kidney, liver, pancreatic islet, lung, or intestine.

Description

PREVENTION OF CHRONIC REJECTION IN SOLID ORGAN
TRANSPLANTATION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/697,459, filed July 7, 2005, the contents of which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention is in the field of solid organ transplantation, and specifically more efficient methods of preventing immune-mediated rejection of said transplanted organs.
BACKGROUND
[0003] The success of solid organ transplantation is limited by rejection of the transplanted organ by the host immune system. Acute graft rejection refers to the immune response immediately following transplantation, and chronic rejection refers to the longer term rejection that is marked by alloreactive antibody formation, leukocyte infiltration and accelerated graft ateriopathy as seen in heart transplant. Although systemic general immune suppression can be used to prevent organ rejection, such generalized immune suppression exposes the subject to opportunistic infections, cancers (e.g. blood cancers) and other undesirable complications including osteoporosis, hypertension, obesity, diabetes, poor wound healing, cushingoid, mood swings, bone marrow suppression, hepatic dysfunction, hair loss, nephrotoxicity, cardiomyopathy, gastrointestinal problems, particularly when used over a long time to combat chronic rejection. The need exists for improved methods of solid organ transplantation that avoid chronic rejection.
[0004] IL-10 is an immunosuppressive modulator that plays important roles in peripheral T-cell tolerance. IL-10 has been shown to skew the cytokine production from ThI to Th2 which is associated with long-survived grafts. By inhibiting synthesis of Thl-differentiating cytokine IL- 12, IL-10 blocks Tl development, production of cytokines INF-γ and IL-2, and therefore prevents potential graft destruction by CTL responses. IL-10 has also been shown to promote apoptosis of alloreactive T cells via the Fas/FasL pathway, which is one of the mechanisms for graft survival. In addition, IL-10 down regulates expression of MHC Class II and co- stimulatory molecules CD40, CD80 and CD86 on APC. Consequently, repetitive stimulation of T cells with alloantigens in the presence of IL-10 induces regulatory T cells producing IL- 10 and TGF-β with suppressive activities and results in prevention of graft rejection.
[0005] IL-10 gene therapy has been tested in various transplant models (Table l). Numbers in Table 1 refer to the literature references describing the relevant studies.
TABLE l
IL-10 Gene Therapy Experiments in Organ Transplantation (Literature
Cited)
[0006] Studies using plasmid DNA and adenoviral vectors encoding IL-10 have demonstrated the effectiveness of IL-10 in acute graft rejection. However, IL-10 expression from plasmid or viral vectors such as adenovirus, herpes virus and retrovirus has achieved limited success in prolonging allograft survival due to limited gene transfer efficiency and transient transgene expression in grafts (3-9, 15). [0007] The need exists for improved methods of IL-IO gene therapy for solid organ transplants that result in sustained local IL- 10 expression sufficient to reduce the likelihood of chronic graft rejection.
SUMMARY
[0008] In one aspect, the present invention relates to the use of recombinant adeno- associated virus (rAAV) vectors to transducer cells of a solid organ to be transplanted with a nucleic acid sequence encoding an immunomodulatory polypeptide, e.g. IL-10, the expression of which reduces the likelihood of rejection of the transplanted organ by the host immune system.
[0009] In another embodiment, in addition to rAAV transduction of a solid organ to be transplanted, the invention further comprises the use of immunomodulatory agents to suppress acute rejection. In one embodiment an immunosuppressive agent is administered at approximately the time of the transplant. In another embodiment an immunosuppressive agent is administered prior to the transplant. In yet further embodiments, immunosuppressive agent(s) are one or more agents selected from the group including, but not limited to, IL-10 and FK506. In other embodiments, treatment with immunomodulatory agent(s) is curtailed or discontinued once rAAV-directed expression of the immunomodulatory polypeptide, e.g. IL-10, has begun.
[0010] In another aspect, the present invention relates to methods of improving the efficiency of solid organ transplantation by administering rAAV vectors encoding IL-10 to an isolated solid organ prior to transplantation of that organ into a subject. In one embodiment, IL-10 is expressed in at least some of the cells of the isolated organ after administration of the rAAV vectors. In another embodiment the expression of IL-10 causes a shift from a Thl-like to a Th2-like immune response. In various embodiments, the solid organ to be transduced is the heart, kidney, liver, pancreatic islet, lung and intestine.
DETAILED DESCRIPTION
[0011] In one embodiment, the present invention is related to the treatment of an isolated solid organ with an rAAV vector encoding an immunomodulatory polypeptide, e.g. IL-10, prior to transplantation of that organ into a subject. The nucleic acid sequence encoding the immunomodulatory polypeptide is referred to herein as a transgene. Expression of the transgene within the cells and tissues of that transplanted organ may delay or/and prevent graft rejection.
[0012] Suitable immunomodulatory polypeptides that may be used in the methods of the present invention include, but are not limited to IL-10, IL-I inhibitors, CD-40 ligand inhibitors, TGF-β, GITR and FOXP3.
[0013] Although AAV vectors offer persistent transgene expression with negligible tissue inflammation, the onset of transgene expression from AAV vectors is normally delayed by 1"2 weeks in comparison to a few hours with adenoviral vectors. Therefore the use of AAV vector may be combined with immunomodulatory agent(s) is administered at approximately the same time as the transplantation, and in other embodiments the immunomodulatory agent(s) is curtailed or discontinued once transgene expression has begun. In yet further embodiments administration of the immunomodulatory agent(s) is discontinued once that transgene is expressed at levels sufficient to prevent graft rejection.
[0014] As used herein, immunomodulatory agent refers to any immunomodulatory substance that is not delivered as a transgene by gene therapy, e.g. a small molecule, peptide or protein. Immunomodulatory agents include, but are not limited to, IL-10 protein, FK506, cyclosporin, rapamycin, azathioprine, mycophenolate mofetil, cyclophosphamide, leflunomide, and corticosteroids. In various embodiments of the present invention, a single immunomodulatory agent may be used, or two or more immunomodulatory agents may be used in combination, either sequentially or concurrently.
[0015] One of skill in the art could readily determine by animal experiments or clinical trials the optimal timing for delivery of immunomodulatory agent(s) to a subject receiving a solid organ transplant according to the methods of the present invention. Similarly, one of skill in the art could perform experiments to determine which of the known immunomodulatory agent(s) is best at preventing acute rejection until rAAV-mediated IL-IO expression begins.
[0016] Whether long term IL-10 expression in a transplanted organ prevents chronic rejection will be measured in part by detection of alloreactive antibody formation, leukocyte infiltration, and accelerated graft arteriopathy as seen in heart transplant.
EXAMPLE 1
USE OF RAAV-IL-10 IN SYNGENEIC HEART AND KIDNEY GRAFTS
[0017] The following experiment is performed to determine the transduction efficiency of AAV2-rat IL-10 (rIL-10) in syngeneic heart and kidney grafts, using AAV-null vector treated rats as controls. This experiment is used to establish the time of onset, the level, and the duration of transgene rIL-10 expression in transplant post ex vivo transduction.
* Anterograde/isolated heart or kidney is perfused with IxIO12 vg vector for 20 minutes in the cold.
* The organ is transplanted back to autologous host.
* Transduction efficiency is determined at days 7, 14, 28, 56 and 180. 1. DNA FISH is performed for transgene rILrlO DNA and IF is performed for rIL-10 protein expression in grafts.
2. Biodistribution is determined by PCR and RT-PCR of rlL- 10 in various tissues including heart, lung, liver, kidney, spleen and PBMC.
3. Systemic rIL-10 production is measured by an ELISA assay of serum rILrlO levels.
TABLE 2
EXAMPLE 2 USE OF RAAV-IL-10 IN HEART AND KIDNEY ALLOGRAFTS
[0018] The following experiment is performed to determine the efficacy of AAV2-rIL"10 transduction in prolonging allograft survival. Groups of rats receive transplanted organs transduced with AAV vectors, as shown in Table 3. rIL-10 protein is administered as an immunomodulatory agent in some experiments to bridge the time lag between transduction and the onset of transgene expression. Because systemic administration of IL-10 has been shown to exacerbate cardiac allograft rejection in mice, the conventional immunomodulator FK506 is administered instead of IL-10 in other experiments up to the time that AAV-mediated IL-10 expression is established. Control experiments include: no treatment; treatment with AAV2-null vectors! and treatment with conventional immunomodulatory agent alone without AAV vectors.
[0019] The following analyses are performed. The duration of graft survival is determined. The expression of ThI cytokines are monokines is measured to determine whether they are down-regulated in AAV2-rIL10-transduced grafts. A cytokine protein chip may be used if necessary to screen for a wider spectrum of cytokines regulated by IL' 10. Finally, the levels of allore active antibodies and leukocyte infiltration are determined, as is the responsiveness of allospecific T cells.
References^
Zhang Y. Claire, et al. Adeno-Associated Virus-Mediated IL-IO Gen Therapy Inhibits Diabetes Recurrence in Syngenic Islet cell Transplantation of NOD Mice Diabetes, 52:708-716, 2003
Goudy Kevin, et al. Adeno-Associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes NOD mice: PNAS 98:13913-13918, 2001
Sen Luyi, et al. Efficiency, efficacy, and adverse effects of adenovirus vs. Liposome-mediated gene therapy in cardiac allografts. Am J Physiol Heart Circ Physiol 281:1433-1441, 2001
Fischer Stefan et al: In Vivo Transtracheal Adenovirus-Mediated Transfer of Human Interleukin-10 Gene to Donor Lungs Ameliorates Ischemia- Reperfusion Injury and Improves Early Posttransplant Graft Function in the Rat Human Gene Therapy 12:1513-1526, 2001
Kenneth E. Drazan, et al.-' Transduction of Hepatic Allograft Achieves Local Levels of Viral IL-10 which Suppress Allore activity in Vitro Journal of Surgical Research, 59, 219-223, 1995
Shoji F et al: Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplant fibrous obliteration in mice Gene Therapy 10:213-218, 2003
Fu Shuang, et al: Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer Prolongs Non-Vascularized Cardiac Allograft Survival American Journal of Transplantation 3:552-567, 2003
Yang Zangong, et al: Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer The Journal of Immunology 168:6479-6485, 2002
Fischer Stefan, et al.: Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis: Journal of Thoracic and Cardiovascular Surgery October:1174- 1180, 2003
Hong Yoo Sun, et al: Localized Immunosuppression in the Cardiac Allograft Induced by a New Liposome-mediated IL- 10 Gene therapy J Heart Lung Transplant 21:1188-1200, 2002
La DeBruyne, et al: Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses Gene Therapy 5: 1079" 1087, 1998 Tung Thomas C, et al: Dual upregulation of Fas and Bax promotes alloreactive T cell apoptosis in IL-10 gene targeting of cardiac allograft Am J Physiol Heart Circ Physiol 285; 964-973, 2003
Hong Chu, et al: Non- Viral Human IL' 10 Gene Expression Reduces Acute Rejection In Heterotopic Auxiliary Liver Transplantation In Rats : Microsurgery 23:432-436, 2003
Itano Hideki, et al: Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplanation: General Thoracic Surgery 122:29-38, 2001
Giuseppe Vassalli et al: Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection European Journal of Cardio-Thoracic Surgery 24:794-806, 2003
Verwaerde C. et al: Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA44'lg inhibits experimental autoimmune uveoretinities Gene Therapy 10: 1970- 1981, 2003
Okada, Y. et al: Does adenovirus-Mediated viral IL-10 Gene Transfer Prolong Survival of Xenogeneic Spheroidal Aggregate- Cultured Hepatocytes? Transplantation Proceedings 32:1021-1023, 2000
Salgar Shashikumark. et al: Viral Interleukin- 10-Engineered Autologous Hematopoietic Stem Cell therapy: A Novel Gene Therapy Approach to Prevent Graft Rejection Human Gene Therapy 15:131-144, 2004

Claims

We claim :
1) A method of performing a solid organ transplant in a subject comprising: administering to a solid organ to be transplanted a recombinant adeno-associated virus (rAAV) encoding an immunomodulatory transgeneJ and
transplanting said solid organ into said subject.
2) The method of claim 1 wherein the immunomodulatory transgene is IL- 10.
3) The method of claim 2, further comprising '• administering an immunomodulatory agent to said subject.
EP06774461A 2005-07-07 2006-06-30 Prevention of chronic rejection in solid organ transplantation Withdrawn EP1903872A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69745905P 2005-07-07 2005-07-07
PCT/US2006/025979 WO2007008485A2 (en) 2005-07-07 2006-06-30 Prevention of chronic rejection in solid organ transplantation

Publications (1)

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EP1903872A2 true EP1903872A2 (en) 2008-04-02

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EP (1) EP1903872A2 (en)
JP (1) JP2009500417A (en)
CN (1) CN101217875A (en)
AU (1) AU2006269487A1 (en)
BR (1) BRPI0614056A2 (en)
IL (1) IL188561A0 (en)
WO (1) WO2007008485A2 (en)

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WO2009145238A1 (en) * 2008-05-27 2009-12-03 国立大学法人名古屋大学 Immunomodulatory agent and use thereof

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WO1998009524A1 (en) * 1996-09-06 1998-03-12 Chiron Corporation Methods and compositions for liver specific delivery of therapeutic molecules using recombinant aav vectors
US20050142111A1 (en) * 2003-12-30 2005-06-30 Agtc Gene Technology Company Ltd. Method to prevent transplant rejection by stable expression of heme oxygenase-1

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See references of WO2007008485A2 *

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JP2009500417A (en) 2009-01-08
WO2007008485A2 (en) 2007-01-18
WO2007008485A3 (en) 2007-03-01
CN101217875A (en) 2008-07-09
IL188561A0 (en) 2008-04-13
AU2006269487A1 (en) 2007-01-18

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