Project Details
Description
There is no one delivery system which is ideal for all proposed gene
therapy protocols. This proposal examines two aspects which would
greatly expand the use of retroviral vectors, in particular those based
on murine retroviruses.
Retroviral vectors have many benefits for introduction of genes,
including an efficient, site-specific viral integration system. One
limitation of murine retroviral vectors is in the ability to infect non-
dividing cells. Recently, the lentivirus class of retroviruses has been
shown to infect both dividing and non-dividing cells. Most recent
success has been in the generation of HIV base vectors, which raise
concern for their overall use gene therapy. In this application, the
knowledge that other retroviruses have adapted for infection of
quiescent cells will be applied to the generation of murine retroviral
vectors which are capable of infecting non-dividing cells.
The research proposes a wide based, systematic approach to generate
murine retroviral vectors which can infect quiescent cells. Three
general schemes are proposed. The first is the insertion of nuclear
localization signals from multiple alternative import pathways into the
viral integrase protein (IN). The second approach is the generation of
IN fusion proteins with proteins known to be nuclear or involved in the
import process. Finally, alternatives MuLV the proteins which are
associated with the preintegrative complex will be modified. The second
specific aim addresses the potential to target integration within the
host genome. Although viral integration occurs site-specifically with
respect to the viral genome, it occurs near randomly in the target DNA.
Preliminary experiments are proposed to test a novel mechanism of
targeting viral integration, using a protein complementation system.
Status | Finished |
---|---|
Effective start/end date | 9/10/98 → 7/31/01 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases
ASJC
- Virology
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