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NEURON-SPECIFIC RETROGRADE TRANSPORT VECTOR

Foreign code F120006745
File No. A301-03WO
Posted date 2012年6月6日
Country 世界知的所有権機関(WIPO)
International application number 2011JP077142
International publication number WO 2012070639
Date of international filing 平成23年11月25日(2011.11.25)
Date of international publication 平成24年5月31日(2012.5.31)
Priority data
  • 特願2010-263148 (2010.11.26) JP
Title NEURON-SPECIFIC RETROGRADE TRANSPORT VECTOR
Abstract The purpose of the present invention is to provide a lentiviral vector system which sustains a high-frequency retrograde transport ability in animal brain and has an increased titer. The present invention relates to a kit for preparing a retrograde transport viral vector and so on, said kit comprising: (1) a packaging plasmid containing the gag and pol genes of HIV-1; (2) a packaging plasmid containing an accessory gene of HIV-1; (3) a transfer plasmid containing a target gene; and (4) an envelop plasmid containing, as an envelope gene, a gene encoding a fused polypeptide, said fused polypeptide comprising a fused extracellular domain comprising the N-terminal region of the extracellular domain of rabies virus glycoprotein (RV-G) and the C-terminal region of the extracellular domain of vesicular stomatitis virus glycoprotein (VSV-G), the transmembrane domain of RV-G or VSV-G, and the intracellular domain of VSV-G.
Outline of related art and contending technology BACKGROUND ART
Non-proliferating (non-replicating) type recombinant vectors is, a gene of interest in the central nervous system (CNS) transport over the long term non-dividing cells and maintain the expression system or the like as vectors for gene therapy for various diseases of many studies used (non-patent document 1-4). In particular, vectors derived from primate HIV-1 (human immunodeficiency virus type 1) as vectors for gene therapy is of value that the best (non-patent document 5-8). However, for vectors integrated into the chromosome is, rats are known to be at risk. In particular, in gene therapy for diseases of the hematologic system example leukemia who have been reported. In gene therapy of liver related diseases, suppressing a risk of the rats, a higher level of safety to develop a vector system, gene transfer can be selectively to nerve cells has been desired.
On the other hand, certain gene for for the treatment of neurodegenerative disorders, nerve endings in the infected site, transported in a retrograde fashion axons, such infection site located at a remote location at the target site is a gene of interest is introduced into the cell body can be a viral vector (Fig. 1) is beneficial.
So far, as the envelope glycoprotein (envelope gene protein), vesicular stomatitis virus (vesicular stomatitis virus: VSV) glycoprotein (VSV-G) (pseudotyped: pseudotyping) using recombinant virus using HIV-1, cynomolgus retrograde transport in the brain has been systems have been developed, retrograde transport of this vector is efficient (non-patent document 9) is not. In the method described in this document, the result was confirmed by immunostaining, injected to the striatum of the monkey recombinant HIV-1 in a retrograde fashion viruses in infected cells of the central nervous system had a slight.
On the other hand, rabies virus (rabies virus: RV) is, more infected the synaptic terminal, transported in a retrograde fashion axons activity that is known. In fact, equine anemia virus RV-G by based on the ability of a non-primate vectors is increased by retrograde transport have been reported (non-patent document 10, patent document 1 and 11).
Further, RV-G pseudotyped lentiviral HIV-1 was reported (non-patent document 3) but, in practice this report in an animal experiment (in vivo) using viral vectors is not performed. In addition, cause the nerves of rabies virus in a one-way, or glycoprotein (Mokola lyssavirus) moko larissa virus VSV-G pseudotyped HIV-1 CNS and in the gene transfer vector has been studied. Glycoprotein or moko larissa virus pseudotyped with the VSV-G vector was injected into the rats nostril HIV-1 as a result, with respect to the retrograde transport the olfactory system, these vectors can be comparable to each other (non-patent document 12). In addition, this document discloses that the viral vector was administered via the striatum has not been described the.
The present inventors have thus far, of the rabies virus glycoprotein gene (RV-G) lentiviruses pseudotyped HIV-1 in vector (vector RV-G/HIV-1) thus produced, various high frequency can be in the region in the brain to allow retrograde gene transfer revealed (Patent Document 2, Hum. Gene Ther., 2007). Further, RV-G intracellular domain of vesicular stomatitis virus glycoprotein (VSV-G) and the substitution of one of the fusion glycoprotein (FuG-B) was prepared. Using this, retain the ability to retrograde transport of high efficiency, and, higher titers of the vectors (functional titer) to construct a system having, retrograde gene transfer significantly enhancing the frequency of successful (Hum. Gene Ther., 2010).
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • Japan Science and Technology Agency
  • Inventor
  • KOBAYASHI Kazuto
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
Reference ( R and D project ) CREST 脳の機能発達と学習メカニズムの解明 領域
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