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TARGETING LENTIVECTOR GENE DELIVERY TO HEMATOPOIETIC STEM
AND PROGENITOR CELLS IN VIVO
by
Leslie Anne Ziegler
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMICAL ENGINEERING)
August 2008
Copyright 2008 Leslie Anne Ziegler
Object Description
| Title | Targeting lentivector gene delivery to hematopoietic stem and progenitor cells in vivo |
| Author | Ziegler, Leslie Anne |
| Author email | labailey@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemical Engineering |
| School | Viterbi School of Engineering |
| Date defended/completed | 2008-06-05 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-06 |
| Advisor (committee chair) | Wang, Pin |
| Advisor (committee member) |
Shing, Katherine Kohn, Don |
| Abstract | Targeted, virus mediated gene delivery holds the potential to treat previously incurable diseases. Gene delivery to the common blood progenitor cells located in bone marrow, hematopoietic stem cells (HSCs), can provide a life-long source of a gene; therefore, a single injection may last a lifetime. Viral vectors are among the most efficient gene delivery machinery. Retrovectors in particular are appealing for gene delivery to HSCs due to low immunogenicity and their ability to stably integrate into the host cell genome. Lentivectors, a type of retrovector, are also able to transduce non-dividing cells. Recently, our group developed a new method to target genes to specific cell types in vivo using lentivectors. In order to target and deliver a gene using a lentivirus, cell binding and fusion must occur. Usually, binding and fusion are coupled at the same glycoprotein. Most previous attempts at targeted gene delivery have involved manipulating this glycoprotein by inserting targeting molecules into different locations within this glycoprotein or adding a ligand or antibody to bridge the virus to the cell. These methods have resulted in low viral titer, most likely due to the interruption of the natural binding or fusion of the virus, and are unacceptable for therapeutic applications. However, separating binding and fusion allows for increased specificity without decreasing the titer. Using an anti-CD34 antibody or stem cell factor (SCF) as a targeting molecule and a bindingdeficient, fusion competent mutant of the Sindbis virus glycoprotein as a fusogen, we have been able to specifically target CD34+ and CD117+ cell lines in vitro. In vivo in a mouse model we have specifically targeted xenografted CD34+ and CD117+ cell lines. We have further shown that both the antibody and fusogen are required for targeted transduction of CD34 and CD117 cell lines. |
| Keyword | gene therapy; lentivector; hematopoietic stem cell |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1320 |
| Rights | Ziegler, Leslie Anne |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Ziegler-20080706 |
| Archival file | uscthesesreloadpub_Volume29/etd-Ziegler-20080706.pdf |
Description
| Title | Page 1 |
| Full text | TARGETING LENTIVECTOR GENE DELIVERY TO HEMATOPOIETIC STEM AND PROGENITOR CELLS IN VIVO by Leslie Anne Ziegler A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMICAL ENGINEERING) August 2008 Copyright 2008 Leslie Anne Ziegler |
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