Targeted Retroviral Vectors for Gene Therapy of Diabetes

Project Details

Description

DESCRIPTION (provided by applicant)

The long-term objective of this proposed research is to develop retroviral
vectors which deliver therapeutic genes for diabetes specifically to liver and
pancreatic beta-cells. The short-term aim of this project is to alter the
cell-binding site of the retroviral surface Envelope protein (Env) such that it
only mediates binding and entry of the retrovirus specifically into liver or
beta-cells. This research develops the use of the feline leukemia virus (FeLV)
Env as the backbone for modification. The FeLV Env is more amenable for this
modification than previously studied Env proteins, such as those of the marine
leukemia viruses, because the FeLV Env encodes a short stretch of amino acids
within its amino terminus that determines receptor specificity. One targeting
strategy employs a library of 106-107 env genes with random amino acids
substituted into this receptor-determining region. The library will be screened
for the ability of am of the random sequences to enable entry specifically into
liver or beta-cells. Preliminary results indicate that Env proteins with novel
targeting specificities can be derived from such a selection screen. A second
strategy is to use a library with a liver-specific peptide substituted into the
receptor-determining region. In this approach, the liver-targeting peptide is
flanked by random amino acids in order to optimize the conformation of the
peptide. This library will be screened for the specific targeting of liver
cells. These strategies differ from earlier approaches to alter retroviral
targeting by the use of bulky antibody fragments or other large cell-binding
ligands. The short peptide sequences being introduced into the FeLV Env in the
project described here should only minimally perturb the Env protein. These
specifically targeted Env proteins will eventually be used to deliver genes
that can ether protect beta cells from immune destruction or induce insulin
expression in liver cells.
StatusFinished
Effective start/end date9/1/018/31/04

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $157,000.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $157,000.00

ASJC

  • Genetics
  • Biotechnology
  • Endocrinology, Diabetes and Metabolism

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