Activity of Fully Deleted Helper-Virus Independent Adenoviral Gene Therapy Vector

Information

  • Research Project
  • 8016076
  • ApplicationId
    8016076
  • Core Project Number
    R43AI081404
  • Full Project Number
    5R43AI081404-02
  • Serial Number
    81404
  • FOA Number
    PA-09-095
  • Sub Project Id
  • Project Start Date
    2/1/2010 - 14 years ago
  • Project End Date
    1/31/2012 - 12 years ago
  • Program Officer Name
    PARK, EUN-CHUNG
  • Budget Start Date
    2/1/2011 - 13 years ago
  • Budget End Date
    1/31/2012 - 12 years ago
  • Fiscal Year
    2011
  • Support Year
    2
  • Suffix
  • Award Notice Date
    1/12/2011 - 14 years ago
Organizations

Activity of Fully Deleted Helper-Virus Independent Adenoviral Gene Therapy Vector

DESCRIPTION (provided by applicant): Numerous diseases are caused by gene defects. The goal of gene therapy is the effective treatment or cure of these diseases by the introduction of the normal gene or repair of the gene defect. A large research effort has been mounted to optimize gene transfer vectors mostly based on adenoviruses and retroviruses. Yet, the initial promise of gene therapy has been undermined by the biology of the commonly used viral vectors: retroviruses are intrinsically mutagenic and oncogenic as they integrate into the human genome;vectors derived from adenoviruses induce vigorous humoral and cellular immune responses that negate the therapeutic success. Isogenis is taking a two pronged approach to the problem of immunogenicity in Adenoviral vectors. First, others have also shown that Adenoviral vectors deleted of viral genes, i.e. fully deleted (fd, gutless) are less immunogenic than vectors containing more viral genes. Despite intensive research, the efficient production of fd Adenoviral vectors still requires the use of 'helper'viruses to deliver crucial Adenoviral genes. Isogenis had learned from its discussion with the FDA (Dr. Stephanie Simek, Deputy Director, Division of Cellular and Gene Therapy) that the use of 'helper'viruses for the production of fd Adenoviral vectors was considered problematic as present purification systems did not deliver preparations with 'helper'virus contamination levels of less than 1-in-3 x 1010 particles. Isogenis has produced a novel fd Adenoviral vector production system that avoids the use of a 'helper'virus and replication-efficient recombinants. Isogenis will use this novel vector architecture to produce clinical gene therapy vectors for the treatment of hemophilia A and ornithine transcarbamylase deficiency (OTCD). The activity of these vectors will be tested in pre-clinical animal models. Second, to overcome any remaining immunogenicity, Isogenis has developed innovative immune inhibitory gene transfer vectors. These employ the highly specific, yet effective immune suppression of the natural "veto" immune inhibitory phenomenon. Briefly, cells expressing CD8 on their surface exert a "veto" on T-cells responding to other antigens on their surface. The activity of these vectors will be tested in pre-clinical animal models. The development of these new Adenoviral vectors is a major step forward in getting gene therapy back on track. PUBLIC HEALTH RELEVANCE: The goal of gene therapy is the cure of the disease by the introduction or repair of the defective gene. In the case of hemophilia A and OTCD, the 'missing'enzyme will be directly delivered to the resident hepatocytes. Gene therapy vectors will have to lead to sustained gene expression in their target tissue to provide a permanent cure. Immune responses directed against vector proteins generally negate any therapeutic effect. Therefore, strategies are being sought that allowed the production of effective gene therapy vectors that did no longer contain vector-derived, i.e. viral, genes. In the case of adenoviral vectors such fully deleted vectors had been designed. There efficient production depended on the use of helper viruses. Yet, the use of a helper virus was considered problematic by the FDA. Present purification systems do not deliver preparations with helper virus contamination levels of less than 1-in-3x1010. In this application, we therefore propose to investigate how w novel set of helper-virus independent fully deleted Adenoviral gene transfer vectors function in vivo.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R43
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    200000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:200000\
  • Funding Mechanism
    SBIR-STTR
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    ISOGENIS, INC.
  • Organization Department
  • Organization DUNS
    160156543
  • Organization City
    AURORA
  • Organization State
    CO
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    800457335
  • Organization District
    UNITED STATES