The sequence of the human genome will lead to the detection of thousands of genes that are uniquely expressed in cancer of the brain as well as other organs. The genes uniquely expressed in brain cancer could be used to guide new forms of diagnosis and therapeutic strategies if it was possible to develop a new technology for imaging gene expression in the brain in vivo. Technology that enables the imaging of gene expression is needed because it will not be possible to subject patients to repeated craniotomies to obtain tissue samples. The only way that specific genes can be imaged is with antisense radiopharmaceuticals. However, these molecules do not cross cell membranes well and do not cross the blood-brain barrier (BBB). It could be possible to use antisense radiopharmaceuticals to image gene expression, if these molecules were transportable through the BBB. This will require the development of brain targeting technology applied to antisense molecules, which is the subject of the present application. In this approach, the antisense radiopharmaceutical is conjugated to BBB drug targeting systems. The targeting vector is a peptidomimetic monoclonal antibody (MAb) to the BBB transferrin receptor (TfR). This MAb undergoes receptor-mediated transcytosis through the BBB via the endogenous BBB TfR. The model antisense molecule that will be used in these studies is a peptide nucleic acid (PNA) because prior work has shown that this type of antisense has ideal characteristics for imaging compared to other antisense molecules. The conjugation of the antisense radiopharmaceuticals to the drug targeting vector is facilitated with the use of avidin- biotin technology. In the R21 phase of this work, the imaging of an endogenous gene will be performed and the target mRNA will be a gene product that is over-expressed in experimental brain tumors. The second phase of these studies (R33) will extend the imaging technologies to include [ 11 l-indium] antisense radiopharmaceuticals and validation of the in vivo imaging with parallel in vitro measurements with in situ hybridization. If successful, these studies will provide the basis for a new technology that enables non-invasive imaging of gene expression in the brain in vivo. This technology could be extended to humans and to other organs. At present, there is no parallel technology that enables the non-invasive in vivo imaging of """"""""any gene in any person,"""""""" which is the goal of this work.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33CA091098-03
Application #
6894945
Study Section
Special Emphasis Panel (ZCA1-SRRB-D (O1))
Program Officer
Baker, Houston
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$324,060
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095