Gene & Cell Therapy Program

J. Michael Mathis, Ph.D.
Professor and Director, Gene Therapy Program
Dept of Cellular Biology and Anatomy
LSU Health Sciences Center
1501 Kings Hwy
Shreveport, LA 71130
Phone: 318.675.4327
Fax: 318.675.5889

Research Interests

We have three major Cancer Gene Therapy projects ongoing in the lab.

Targeted Oncolytic Virotherapy for Breast Cancer. Last year, more than 200,000 women in the United States were diagnosed with breast cancer. It is the most common malignancy and the second leading cause of cancer death in women. Therefore, novel therapies are sorely needed. The goal of our project is to engineer a version of the common cold virus, called an adenovirus to seek and destroy cancer cells while leaving healthy tissue unscathed.  Although attempted in the past, the concept of turning viruses loose on cancer was abandoned because of toxicity and inefficacy. However, the virotherapy approach has reemerged with great promise, in large part because of better understanding of and the ability genetically to modify viruses.

Mathis Lab

The goal of this project is to progress an advanced generation of virotherapy agent using the biology of breast cancer to target this disease. To produce an adenovirus virotherapy agent that targets breast cancer, we have modified a functional gene called E1A within the adenovirus that is vital for efficient multiplication, such that it is only active in tumor cells but not normal cells. We have added a second modification such that the E1A protein is only produced in tumor cells. Finally, we have added a third modification such that the adenovirus is efficiently taken up by tumors but not by liver where the majority of toxicity arises.

This proposed approach is novel; we are testing a conceptually new approach to provide a combination of modifications that are most appropriate for the majority of breast cancers to enhance substantially adenovirus-based virotherapy. Using these three approaches in combination, we propose to develop and validate a completely new class of virotherapy agents.  We anticipate that the pre-clinical studies in animals will lead directly to a clini-cal trial when completed.

Oncolytic Adenovirus

Mesenchymal Stem Cells as a Vehicle for Targeted Virotherapy Delivery. In the United States, breast cancer remains the most common malignancy and the second leading cause of cancer death in women. In some women, breast cancer is a local disease without spread. Such early breast cancers are usually diagnosed by screening mammography and are highly curable with local or regional treatment alone. However, most women with primary cancer have subclinical metastases, and in a high percentage of those treated with apparently curative surgery, distant metastases ultimately develop. The clinical course of metastatic breast cancer is variable.

Chemotherapy, hormonal therapy, radiotherapy, and limited surgery are all used in the treatment of women with metastatic breast cancer, although the overwhelming majority of these women will die of their disease. In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed.

Virotherapy is an exciting therapeutic approach for treating cancer in which the replicating virus itself is the anticancer agent. The goal of our project is to engineer a version of the common cold virus, called an adenovirus to seek and destroy cancer cells while leaving healthy tissue unscathed.  However, efficient virus delivery to the tumor site has been a major limitation. To overcome this, we will use an approach somewhat analogous to a“Trojan horse”, in which cell carriers having tumor homing activity will be exploited to chaperone virus delivery to tumor sites.

Systemically administered CRAd loaded human mesenchymal stem cellsWe propose the use of adult human mesenchymal stem cells (hMSCs) as carriers of oncolytic viruses. MSC are bone marrow-derived non-hematopoietic precursor cells that can be easily harvested from patients and grown. When systemically administered back, these cells can home to tumor sites, preferentially survive, and proliferate in the presence of cancer cells and become incorporated into the tumor architecture.

Our work, investigating systemic administration of hMSC carriers to deliver CRAds to breast tumors, constitutes a novel therapeutic paradigm for breast cancer that couples adult stem cell therapy with virotherapy. Completion of this work will advance a promising new therapy for treating distant metastatic disease.

The use of non-invasive PET-based imaging to monitor oncolytic adenovirus replication and localization. In view of the limited success of available treatment modalities for breast cancer, alternative and complementary strategies need to be developed. Virotherapy marks an innovative approach in the development of new treatment regimes, in which a replicating virus itself is the anti-cancer agent. Virotherapy employing oncolytic adenoviruses represents a promising targeted intervention relevant to a wide array of neoplastic diseases. The ability of oncolytic adenoviruses and other replicative agents to eradicate tumors critically depends on two key functions, efficient replication and spread within the tumor. A monitoring system that can quantitatively and dynamically capture the replication and spread of these oncolytic viruses would be a useful assessment tool for the development of these agents as well as for their application in patients.

A genetic adenovirus labeling approach was conceived with these features in mind. In this regard, the carboxy-terminus of the minor capsid protein pIX has been defined as a locus capable of presenting incorporated ligands on the virus capsid surface. Specifically, the incorporating of the imaging motif enhanced green fluorescent protein (EGFP) has introduced the concept that functional motifs can be incorporated within the adenoviral capsid. Based on this feasibility, we sought to exploit the possibility of incorporating additional functional proteins at the capsid protein pIX.

For a more clinically relevant monitoring system, we considered the possibility of adapting our oncolytic adenoviruses for compatibility with imaging protocols such as positron emission tomography (PET). This radiological imaging method is routinely used in the clinic for highly sensitive diagnosis of disease with no limits on signal depth. PET imaging has been widely exploited for imaging analysis of gene therapy strategies in small animal models and more recently in human clinical trials.

MicroPETFor PET imaging, we used the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene for the alternative display on the capsid protein pIX. The HSV-1 TK gene has been utilized both for molecular chemotherapy approaches in the context of cancer gene therapy applications and for PET-based imaging strategies. In addition, the 18F-FHBG substrate has recently been FDA approved as an IND agent for use in PET imaging.

Our studies demonstrate the ability to rescue viable adenoviral particles that display functional HSV-1 TK as a component of their capsid surface. We show that this genetic capsid labeling strategy provides a direct approach for dynamic assessment of oncolytic adenoviruses. Furthermore, the determination of an expanded upper limited of incorporable proteins on pIX highlights its unique utility as a locale for functional vector components. In summary, our PET imaging strategy can provide a means for clinically relevant non-invasive real-time monitoring of adenovirus-based virotherapy interventions with the possibility of detecting both localized and disseminated neoplastic diseases.

Selected Publications