HIV GENE THERAPY WITH RNA INHIBITORS

Project: Research project

Project Details

Description

This NCDG proposal represents an integrated series of preclinical studies
designed to develop an effective treatment for HIV patients via
transplantation of genetically modified, viral resistant, stem cells. The
three research projects of this program represent a systematic and
thorough approach to address the current limitations of this emerging
technology and utilize novel strategies that have been developed in the
laboratories of the principal investigators. Project I will develop potent
RNA-based inhibitors with primary emphasis on the use of ribozymes.
However, unlike the current studies which employ the use of trans-cleaving
ribozymes, Project I will develop the use of trans-splicing ribozymes
which offer critical advantages over conventional ribozymes: the ability
to follow ribozyme activity in the cell and hence systematically improve
ribozyme function in vivo, and the ability to generate trans-dominant
inhibitors which should further enhance their antiviral potency. Project
II will assess the function of HIV inhibitors generated in Project I in
monocyte/macrophage and CD4+ T cells derived from transduced stem cells,
and will develop methods to improve retroviral delivery of HIV inhibitors
into hemopoietic stem cells, with the emphasis on identifying conditions
which preserve the undifferentiated phenotype of the vector transduced
cells. A novel and simple paradigm using multiparameter FACS analysis
developed by the P.I. of Project II, is a critical component in the
proposed studies. In Project III, novel methods will be developed
incorporating a new proprietary technology (termed Strand Displacement
Amplification) developed at Becton Dickinson by the PI of Project III to
measure in situ the presence of vector and HIV sequences. Coupled with
phenotypic and functional characteristics of the genetically modified
cells, it will provide sensitive, accurate, and quantitative information
about the effectiveness of HIV gene therapy strategies in clinical
settings. This information will be critical for the rational design of
improved vectors, inhibitors, transduction protocols, and the design of
new clinical studies.
This NCDG program is characterized by extensive and close interactions
between investigators with complementary and unique expertise at Duke
University, the University of Virginia, and Becton Dickinson
Immunocytometry Division. This interaction provides a critical mass of
diverse scientific and medical talent collectively focused on developing
effective gene therapy based treatments for HIV infection and AIDS.
StatusFinished
Effective start/end date4/1/973/31/01

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $629,625.00

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