Mutated adeno-associated virus capsid proteins, AAV particle comprising same and liver directed AAV vector gene therapy
A capsid protein, AAV6 technology, applied in gene therapy, virus/phage, virus, etc.
Pending Publication Date: 2021-12-31
FRAUNHOFER GESELLSCHAFT ZUR FOERDERUNG DER ANGEWANDTEN FORSCHUNG EV
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[0069] Properties of MLIV capsid variants
[0070] Prior to AAV peptide display library selection, the library was pre-cleared of HSPG-bound capsid variants by heparin affinity column purification. In the library, the insert was located between positions 587 and 588 of SEQ ID No.2. After in vivo AAV peptide display library selection in two different mouse models, capsid variants accumulated in liver tissue were named MLIV* library (Hepa129 transplantation) and MLIV library (TGF-α / c-myc transgenic ). 92 candidate variants for transplantation and 84 candidate variants for transgenic mouse models have been identified. The most abundant variants in each of these two libraries were named MLIV1 (MLIV*) (SEQ ID No. 13) and MLIV3 (MLIV) (SEQ ID No. 14), respectively, and were characterized in detail. For in vivo evaluation, MLIV1 and MLIV3 were produced as recombinant (r)AAV vectors expressing the luciferase transgene cassette. Transgene expression is controlled by a ubiquitously ...
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The present invention relates in a first aspect to a mutated adeno-associated virus (AAV) capsid protein or fragment thereof having an insert composed of an oligopeptide optionally having further amino acids representing linker sequences flanking both sites of the oligopeptide. These mutated AAV capsid proteins are more efficient in targeting hepatic tissue, hepatocytes, hepatic cells and cell lines or hepatocellular carcinoma (HCC) with partially higher specificity. Further, a mutated AAV particle comprising the mutated AAV capsid protein according to the present invention is provided. In addition, a nucleic acid encoding the mutated AAV capsid protein according to the present invention is identified together with a corresponding nucleic acid vector, in particular, a plasmid. In addition, a host cell containing the nucleic acid vector or the nucleic acid molecule according to the present invention. Further, a use of the AAV particle or the nucleic acid or the nucleic acid vector according to the present invention in the manufacture of an AAV particle, or in the manufacture of a medicament for gene therapy is described. Moreover, protein, particle molecules as well as nucleic acid vectors for use in targeting hepatocytes and / or HCC are described. In particular, the components for use in treating diseases involving hepatocytes or for treating HCC are disclosed, in particular, for use in gene therapy, e.g. for use in a transfer of a gene of interest into hepatocytes, heptatic tissue or HCC.
Description
technical field [0001] The present invention relates in a first aspect to a mutated adeno-associated virus (AAV) capsid protein or a fragment thereof having an insert consisting of an oligopeptide optionally further having at both ends of the oligopeptide a linker representing sequence of amino acids. These mutated AAV capsid proteins were more effective in transferring genetic material to liver tissue, hepatocytes, hepatic cells and cell lines, or hepatocellular carcinoma (HCC), and partially improved The tropism of these cell types. Further, mutant AAV particles comprising mutant AAV capsid proteins of the invention (either homogeneously or as a mixture) are provided. In addition, nucleic acids encoding mutant AAV capsid proteins of the invention are identified together with corresponding nucleic acid vectors, particularly plasmids. In addition, host cells containing a nucleic acid vector or nucleic acid molecule of the invention are provided. Further, use of the AAV par...
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IPC IPC(8): C07K14/015C12N15/35C12N5/10C12N15/86C07K14/005C12N15/10
CPCC07K14/005C07K2319/33C12N15/1037C12N15/86C12N2750/14122C12N2750/14145A61K48/00A61P1/16C12N2750/14143A61K48/005
Inventor 希尔德加德·贝宁娜嘉·梅曼玛丽亚·冈萨雷斯·卡莫纳克里斯坦·P·施特拉斯堡安娜贝利·沃格特阿尔布雷克特·皮尔珀乔基姆·施瓦贝尔卡琳·休伯埃哈德·塞弗里德
Owner FRAUNHOFER GESELLSCHAFT ZUR FOERDERUNG DER ANGEWANDTEN FORSCHUNG EV