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Lentiviral-MGMT gene transfer into hematopoietic stem cells

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42CA128269-01A2
Agency Tracking Number: R42CA128269
Amount: $2,652,660.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NCI
Solicitation Number: PHS2010-2
Solicitation Year: 2010
Award Year: 2010
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
910 Clopper Road
Gaithersburg, MD -
United States
DUNS: 600855105
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (216) 844-8562
Business Contact
Phone: (216) 368-4510
Research Institution
 Case Western Reserve University
10900 Euclid Ave
Cleveland, OH 44106-7015
United States

 () -
 Nonprofit College or University

DESCRIPTION (provided by applicant): Therapeutic stem cell gene transfer relies on long-term gene expression achieved by integration of new DNA into the cellular genome. Current clinical trials featuring oncoretroviruses have encountered a number of roadblocks that include low levels of gene transfer, poor expression, and a recognized preferential insertion near promoter regions that increases the chance for insertional mutagenesis and leukemia. This proposal will link the advances made at Lentigen Corp. in large scale production of the newest generation lentiviral vectors (LV) with the clinical need for transferring the MGMT gene into hematopoietic stem cells. The goal of this application is to optimize the safety of lentiviral gene transfer of MGMT using preclinical assays followed by a clinical trial using this vector in cancer patients. Expression of the MGMT (O6-methylguanine-DNA- methyltransferase) enzyme has been established as an effective method for hematopoietic progenitor (HP) selection in vivo. The MGMT gene product (also known as AGT, O6-alkylguanine-DNA-alkyltransferase) repairs DNA damaged by alkylating agents. Hematopoietic progenitor cells (HP) can be transduced with a vector containing MGMT and selected for in vivo by administration of a DNA damaging drug therapy, i.e. the alkylating agent Temozolomide, whose potency is increase by co-administration of O6-benzylguanine (BG), a therapeutic inhibitor of the naturally occurring AGT. Using a well-characterized singe point mutation of MGMT, P140K, that is resistant to the inhibitory effects of BG, it is possible to selectively protect HP from the drug combination, providing a unique enrichment strategy for multilineage progenitors in vivo. LVs, a subclass of retroviral vectors, offer several advantages over oncoretroviral vectors including increased transduction efficiencies, long-term gene expression without silencing, and decreased risk of insertional oncogenesis. In Phase I of this application we will generate cGMP vector with improved safety characteristics, analyze the insertion site frequency and preference, and create a publically available database to share this information with other investigators and regulatory agencies. This will set a new standard in the field for sharing data generated from the use of a clinical gene vector with human cells. In the Phase II portion of this application, a clinical trial designed to demonstrate safe use of lentiviral vector with the potential to improve outcomes for patients with advanced glioma, will be initiated. This trial will be the first in man study of in vivo stem cell selection mediated by a drug resistance gene. This trial is of importance not only for patients with glioma, but as means to demonstrate the effective development of a platform for selecting gene-modified stem cells that could also be used for the correction of numerous monogenic disorders. PUBLIC HEALTH RELEVANCE: This proposal is a combined phase I and phase II application, Fast-Track, that will evaluate lentiviral gene vectors expressing the MGMT gene in pre-clinical models and in a clinical trial for glioma. The goal of this application is to optimize the safety of lentiviral gene transfer of MGMT. Demonstration of the safe use of this lentiviral vector in clinical studies will open the door to the treatment of not only glioma, but other malignancies in which hematotoxicity is a major side-effect, or in which malignant stem cells are replaced by donor-derived (allogeneic) or patient-derived (autologous) stem cells that can be selected for in vivo. Thus, this proposal represents a first step in improving the efficacy of stem cell therapeutics by providing the means to increase the number of cells carrying the gene to greater and potentially therapeutic levels.

* Information listed above is at the time of submission. *

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