公开(公告)号：EP1196544A2

公开(公告)日：2002-04-17

申请号：EP00965872.5

申请日：2000-07-19

申请人： Crucell Holland B.V.

发明人： HOEBEN, Robert, C. ,  BOUT, Abraham ,  VALERIO, Domenico ,  VAN DER EB, Alex, J. ,  SCHOUTEN, Govert ,  FALLAUX, Frits, J.

IPC分类号： C12N5/10 ,  C12N15/861 ,  A61K48/00

CPC分类号： C12N7/00 ,  A61K48/00 ,  C07K14/005 ,  C12N15/86 ,  C12N2710/10322 ,  C12N2710/10343 ,  C12N2710/10352 ,  C12N2830/42

摘要： The problem of replication competent adenovirus in virus production is solved in that we have developed packaging cells that have no overlapping sequences with a new basic vector and thus are suited for safe large scale production of recombinant adenoviruses one of the additional problems associated with the use of recombinant adenovirus vectors is the host-defense reaction against treatment with adenovirus. Another aspect of the invention involves screening recombinant adenovirus vector lots, especially those intended for clinical use, for the presence of adenovirus E1 sequences, as this will reveal replication competent adenovirus, as well as revertant E1 adenoviruses. It is also an aspect of the present invention to molecularly characterize the revertants that are generated in the newer helper/vector combinations.

公开(公告)号：EP0870044B1

公开(公告)日：2004-04-14

申请号：EP96940158.7

申请日：1996-11-29

申请人： Crucell Holland B.V.

发明人： EINERHAND, Markus, Peter, Wilhelmus ,  VALERIO, Domenico

IPC分类号： C12N15/85 ,  C12N5/10 ,  C12N15/864

CPC分类号： C12N15/86 ,  C07K14/005 ,  C12N15/85 ,  C12N2750/14122 ,  C12N2750/14143 ,  C12N2830/003 ,  C12N2830/006

摘要： The invention is in the field of recombinant genetic materials, especially for use in gene therapy. Vectors used for transferring additional genetic information to cells in the field of gene therapy are often based on viruses. A group of viruses which has been proposed to use for transfection is the group of parvoviruses, in particular the use of adeno associated virus has been proposed. The invention provides improved methods and means for gene therapy and for preparing products to be used in gene therapy using parvovirus based materials. The invention particularly provides regulated expression of genes under control of the combination of a repressor moiety and an activator moiety, particularly for expression of products which are toxic to the host cell in which they are expressed. In this way it is possible to achieve stable transfection for expression of parvovirus toxic proteins so that amongst others a packaging cell line for producing recombinant parvovirus, in particular adeno associated virus is provided as well as virus produced therewith.

公开(公告)号：EP0833934B2

公开(公告)日：2012-08-15

申请号：EP96917735.1

申请日：1996-06-14

申请人： Crucell Holland B.V.

发明人： FALLAUX, Frits, Jacobus ,  HOEBEN, Robert, Cornelis ,  BOUT, Abraham ,  VALERIO, Domenico ,  VAN DER EB, Alex, Jan

IPC分类号： C12N15/861 ,  C12N5/10

CPC分类号： C12N7/00 ,  A61K48/00 ,  C12N15/86 ,  C12N2710/10321 ,  C12N2710/10343 ,  C12N2710/10351 ,  C12N2710/10352 ,  C12N2830/00 ,  C12N2830/15 ,  C12N2830/42 ,  C12N2830/60

摘要： The invention provides improved methods and products based on adenoviral materials which can advantageously be used in for instance gene therapy. In one aspect an adenoviral vector is provided which has no overlap with a suitable packaging cell line which is another aspect of invention. This combination excludes the possibility of homologous recombination, thereby excluding the possibility of the formation of replication competent adenovirus. In another aspect an adenovirus based helper construct which by its size is incapable of being encapsidated. This helper virus can be transferred into any suitable host cell making it a packaging cell. Further a number of useful mutations to adenoviral based materials and combinations of such mutations are disclosed, which all have in common the safety of the methods and the products, in particular avoiding the production of replication competent adenovirus and/or interference with the immune system. Further a method of intracellular amplification is provided.

公开(公告)号：EP0833934B1

公开(公告)日：2004-10-06

申请号：EP96917735.1

申请日：1996-06-14

申请人： Crucell Holland B.V.

发明人： FALLAUX, Frits, Jacobus ,  HOEBEN, Robert, Cornelis ,  BOUT, Abraham ,  VALERIO, Domenico ,  VAN DER EB, Alex, Jan

IPC分类号： C12N15/861 ,  C12N5/10

CPC分类号： C12N7/00 ,  A61K48/00 ,  C12N15/86 ,  C12N2710/10321 ,  C12N2710/10343 ,  C12N2710/10351 ,  C12N2710/10352 ,  C12N2830/00 ,  C12N2830/15 ,  C12N2830/42 ,  C12N2830/60

摘要： The invention provides improved methods and products based on adenoviral materials which can advantageously be used in for instance gene therapy. In one aspect an adenoviral vector is provided which has no overlap with a suitable packaging cell line which is another aspect of invention. This combination excludes the possibility of homologous recombination, thereby excluding the possibility of the formation of replication competent adenovirus. In another aspect an adenovirus based helper construct which by its size is incapable of being encapsidated. This helper virus can be transferred into any suitable host cell making it a packaging cell. Further a number of useful mutations to adenoviral based materials and combinations of such mutations are disclosed, which all have in common the safety of the methods and the products, in particular avoiding the production of replication competent adenovirus and/or interference with the immune system. Further a method of intracellular amplification is provided.

公开(公告)号：EP0938578B1

公开(公告)日：2004-02-04

申请号：EP97913537.3

申请日：1997-11-19

申请人： Crucell Holland B.V.

发明人： EINERHAND, Markus, Peter, Wilhelmus ,  VALERIO, Domenico

IPC分类号： C12N15/86 ,  C12N5/10 ,  A61K48/00

CPC分类号： C12N15/86 ,  A61K38/00 ,  A61K48/00 ,  C07K14/805 ,  C12N2750/14143

摘要： Genetic modification of pluripotent hemopoietic stem cells of primates (P-PHSC) by transduction of P-PHSC with a recombinant adeno-associated virus (AAV). The genome of the recombinant AAV comprises a DNA sequence flanked by the inverted terminal repeats (ITR) of AAV. The DNA sequence will normally comprise regulatory sequences which are functional in hemopoietic cells and, controlled by these regulatory sequences, a sequence coding for a protein or RNA with a therapeutic property when introduced into hemopoietic cells. Preferred examples of DNA sequences are the human lysosomal glococerebrosidase gene, a globin gene from the human β-globin gene cluster, a DNA sequence encoding an RNA or protein with anti-viral activity, the α1-antitrypsin gene and the human multidrug resistance gene I (MDRI). The invention provides for effective gene therapy with PHSC of primates, in particular humans.