Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1998-07-31
2000-07-04
Guzo, David
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4353201, 435455, 435456, 4352351, 435325, 435366, 435371, 435372, 530350, 536 231, 536 245, C12P 2100, C12P 2102, C12N 15861, C12N 1563, C12N 510
Patent
active
060837209
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a native or recombinant adenoviral protein complex, to a pharmaceutical composition comprising the said protein complex, and to their application in the treatment (medicaments) and prevention (vaccines) of human and animal diseases. The said protein complex is especially capable of dispensing nucleic sequences, proteins, peptides or chemical substances of interest to suitable target cells.
The present invention likewise relates to expression vectors of the said protein complex.
The adenoviruses form a family of DNA animal viruses gathering together more than 90 serotypes infecting different species, including nearly 50 different human serotypes. The cellular tropism of the adenoviruses results in the infection of the respiratory, gastrointestinal and urinary tracts and of the eyes.
These viruses are responsible for 3% of all infections in man, for 10% of infantile pneumonias and for 15% of intestinal infections in children.
The adenovirus particle is relatively complex and comprises several sub-structures; in particular, the external part or capsid is formed mainly of three proteins: the hexon, the penton base and the fibre (see FIG. 1).
The penton, a non-covalent complex formed of a trimeric protein, the fibre, and of a pentameric protein, the penton base, forms the vertices of the viral icosahedron.
Each of the two proteins forming the penton play a fundamental role in infection: the fibre allows the attachment of the virion to a cell receptor; the penton base allows the internalization of the virion, probably owing to the interaction with the cell integrins (linkage with the integrins, vitronectin and fibronectin receptors, by the intermediary of the arg-gly-asp sequence present at the level of the penton base) (Wickham et al., Cell, 1993, 73, 309-319). In addition, observations exist which suggest that the penton base has an endosomolytic activity, allowing the escape into the cytoplasm of molecules co-internalized with the virus (Seth et al., Virus Attachment and Entry into Cells, 1986, Ed. R. L. Crowell & K. Lonberg-Holm, 191-195).
The binding of the adenoviruses to the cells and their internalization are thus two events which are distinct but which cooperate.
The capacity to infect various quiescent cells makes the adenovirus a vector of choice for gene therapy.
The methods currently employed are based on the repeated administration of recombinant adenoviruses, which are deficient for replication, carrying the target gene (PCT International Applications WO 95/02697 and WO 95/14101, in the name of Rhone-Poulenc Rorer SA).
However, the recommended treatments with such deficient adenoviruses have at least the following disadvantages:
risk of restoration in trans of the pathogenicity of the recombinant virus in a subject treated and simultaneously infected by a wild adenovirus;
immune and inflammatory reactions during the repeated administration of the recombinant adenovirus, due to the massive introduction of viral particles bringing in foreign proteins, which curb their use as a gene therapy vector in man.
To avoid such disadvantages, it has been proposed to use only the penton or the penton base, independently of the rest of the genome of the adenovirus, to facilitate the transfer of exogenic genes into host cells (PCT International Application WO 94/17832, in the name of The Scripps Research Institute). Although such an approach has advantages with respect to the recombinant adenoviruses which are deficient for replication, such structures (penton or penton base) are fragile, especially the penton base, which can be destroyed by proteolysis.
As a consequence, the Applicant has the aim of providing a vector which can be used in gene therapy which answers the needs of practice better than the vectors of the prior art; such a vector does not have either the disadvantages of recombinant adenoviruses, or the fragility of the penton or of the penton base, such as specified above.
The present invention relates to an adenoviral protein complex, characterized in that it is fo
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Chroboczek Jadwiga
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