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Aav vector compositions and methods for gene transfer to cells, organs and tissues

a technology of aav and composition, applied in the direction of drug composition, virus/bacteriophage, extracellular fluid disorder, etc., can solve the problems of need for repeated infusion, cost of treatment, risk of anti-therapeutic factor immune response,

Inactive Publication Date: 2015-04-23
THE CHILDRENS HOSPITAL OF PHILADELPHIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text discusses the development of gene-based therapies for hemophilia, a bleeding disorder. The therapeutic approach involves the intravenous administration of recombinant clotting factor either on demand or prophylactically. However, this treatment has several drawbacks such as the need for repeated infusions, the cost of the treatment, and the risk of developing immune responses. To address these issues, gene-based therapies have been developed using adeno-associated virus (AAV) vectors. AAV-Rh74 and related vectors have been shown to efficiently deliver genes in humans and can be used in a greater percentage of humans compared to other AAV serotypes. Additionally, AAV-Rh74 can be produced in large amounts for more prevalent clinical diseases. The technical effects of this patent text are the development of safer, efficient, and cost-effective gene-based therapies for hemophilia.

Problems solved by technology

However, this therapeutic approach has several drawbacks such as the need for repeated infusions, the cost of the treatment, the risk of developing anti-therapeutic factor immune responses, and the risk of potentially fatal bleedings.

Method used

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  • Aav vector compositions and methods for gene transfer to cells, organs and tissues
  • Aav vector compositions and methods for gene transfer to cells, organs and tissues
  • Aav vector compositions and methods for gene transfer to cells, organs and tissues

Examples

Experimental program
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Effect test

example 1

[0104]This example includes a description of various materials and methods.

[0105]Mice:

[0106]Male C57BL / 6J (WT) mice 8-10 weeks of age, n=5 per experimental group. The dog is a HB dog from the University of North Carolina Chapel Hill colony carrying a missense mutation in the FIX gene (Evans et al., Proc Natl Acad Sci USA 86:10095 (1989)).

[0107]AAV Vector Constructs:

[0108]The in vivo studies in mice were performed using a construct expressing human FIX under the control of the ApoE-hAAT liver specific promoter. The study in dogs used a nearly identical promoter and the canine FIX transgene.

[0109]Gene Transfer Methodology:

[0110]All vectors were delivered intravenously. In mice via the tail vein (a volume of 200 microliters per mouse was administered, vector was diluted in PBS). In dogs the vector was delivered via the saphenous vein.

[0111]FIX Expression Determination:

[0112]ELISA was used to measure FIX levels. In mice, the human FIX ELISA antibody pair (capture and secondary) is from ...

example 2

[0120]This example includes a description of human FIX gene transfer animal (Mice) studies and FIX expression after gene transfer.

[0121]C57BL / 6 mice (n=5 per group) were injected via the tail vein with AAV vectors bearing the Factor IX (FIX) gene (2.510 vector genomes per mouse) under the control of a liver-specific promoter. Human FIX transgene product (protein) plasma levels in the mice were determined by ELISA at week 1, 2, and 4 post gene transfer, and are illustrated in FIG. 1. AAV-Rh74 showed the highest level of transgene expression in the animals.

example 3

[0122]This example includes a description of animal studies and data demonstrating effective AAV-Rh74 mediated delivery of FIX at therapeutic levels in hemophilia dogs.

[0123]In brief, hemophilia B dogs were infused intravenously (IV) though the saphenous vein with 3×1012 vector genomes per kg of weight. Expression of the therapeutic FIX transgene was driven by a liver specific promoter. Vectors and FIX levels were monitored by ELISA. Canine FIX plasma levels are shown in FIG. 2. AAV-Rh74 and AAV8 performed roughly equally in hemophilia B dogs, and both were superior to AAV6.

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Abstract

The invention relates to adeno-associated virus (AAV) serotype AAV-Rh74 and related AAV vectors, and AAV-Rh74 and related AAV vector mediated gene transfer methods and uses. In particular, AAV-Rh74 targets polynucleotides to cells, tissues or organs for expression (transcription) of genes encoding therapeutic proteins and peptides, and polynucleotides that function as or are transcribed into inhibitory nucleic acid sequences.

Description

RELATED APPLICATION INFORMATION[0001]This application is the National Phase of International Application No. PCT / US2013 / 026695, filed Feb. 19, 2013, which designated the U.S. and that International Application was published under PCT Article 21(2) in English, which claims priority to Application Ser. No. 61 / 600,415, filed Feb. 17, 2012, all of which applications are expressly incorporated herein by reference in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 14, 2014, is named CHOP—0433686_ST25.txt and is 19,644 bytes in size.INTRODUCTION[0003]Genetic disorders, caused by absence or a defect in a desirable gene (loss of function) or expression of an undesirable or defective gene or (gain of function) lead to a variety of diseases. One example of a loss of function genetic disorder is hemophilia, an ...

Claims

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Application Information

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IPC IPC(8): C12N15/86
CPCC12N2750/14143C12N15/86A61P43/00A61P7/04A61K48/00
Inventor HIGH, KATHERINE A.MINGOZZI, FEDERICOSUN, JUNWEIJOHNSON, PHILIP
Owner THE CHILDRENS HOSPITAL OF PHILADELPHIA
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