$4.7 Million To Support Gene Therapy Research and Clinical Trials at IU School of Medicine

Indianapolis -- One of the country's first three Core Centers of Excellence in Molecular Hematology is being established at the Indiana University School of Medicine through a $4.7 million grant from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK).

The grant will support basic research and the application of this research to clinical trials using gene therapies for childhood leukemias, adult and child cancers, and a variety of genetic blood diseases and metabolic disorders. Blood and blood-related diseases are likely to be among the first maladies treated by gene therapy, because blood is extremely accessible.

Most medical research funding from the federal government supports either specific research projects or patient trials. This new grant, however, supports shared "high-tech" facilities, also called cores, that can be used by many researchers as they work to uncover the underlying causes of blood and blood-related diseases and bring them to the patient's bedside. The other two molecular hematology core centers will be located at Boston Children's Hospital/Harvard University and the Fred Hutchison Cancer Research Center.

The five cores within the new IU School of Medicine Core Center of Excellence in Molecular Hematology Center are the Stem Cell Laboratory Core, the Vector Production Facility Core, the Mouse Core, the Cell Molecular Biology Core and the Gene Therapy Working Group Core.

"These cores are both mature versions of existing facilities supported by a previous NIDDK grant and extensions of those facilities to further support the development of gene transfer technology into human trials," says David A. Williams, M.D., director of the new molecular hematology center.

In the Stem Cell Lab Core, directed by Rafat Abonour, M.D., blood and bone marrow samples are processed and stem cells can be isolated and manipulated for human trials. The Vector Production Facility Core, directed by Kenneth Cornetta, M.D., produces genetically engineered viruses that can be used as delivery vehicles to deliver human gene therapy.

A special strain of mice, which are so immunodeficient that researchers can put human blood into them to study human blood diseases, is the most important aspect of the Mouse Core directed by Wade Clapp M.D. The Cell and Molecular Biology Core, directed by Mark Kelley, Ph.D., analyzes samples from various clinical trials at a molecular level.

The unique Gene Therapy Working Group Core, directed by James Croop, M.D., is comprised of physicians, scientists and others who meet weekly to review ongoing gene therapy trials and ideas, as well as pre-clinical studies that are leading to new gene therapy trials."

"I think this funding, which also provides for young investigator faculty development, is exciting and important," says Dr. Williams, Freida and Albrecht Kipp Professor of Pediatrics at the IUSM and a Howard Hughes Medical Institute Investigator. "It allows a large number of IUSM faculty members to continue the development and implementation of treatment modalities for devastating diseases in both children and adults." Sharing the core facilities allows the pooling of knowledge as well as financial resources.

Initially the center is focussing on three gene therapy trials - two in cancer and one for a rare genetic disorder, Chronic Glanulomous Disease (CGD).

In an ongoing cancer trial, Dr. Abonour is using fragments of fibronectin, a genetically engineered human protein, to enhance the transport of a retrovirus into normal bone marrow cells of patients with advanced germ cell malignancies who have failed conventional treatment.

Fibronectin, which was developed at the Herman B Wells Center for Pediatric Research at the IU School of Medicine, acts as the glue that allows the retrovirus to bind to the therapeutic gene MDR-1. Clinical development of this patented technique is occurring in collaboration with Takara Shuzo Co., Ltd., a Japanese biotechnology firm. With the introduction of the MDR-1 into bone marrow cells, the researchers are attempting to shield normal cells from the additional chemotherapy needed by patients who have not responded to initial chemotherapy, radiation and bone marrow transplantation. Early results show that nearly 10 percent of the stem cells contained the gene more than one year after treatment. In previous studies not using fibronectin fragments, less than one percent of the stem cells contained the manipulated gene.

A second gene therapy trial targeting brain tumors in adults and children started recently. In this trial, the blood stem cell is modified genetically in an attempt to make it resistant to the toxic effects of a specific chemotherapy agent previously shown useful in treating brain tumors.

Gene therapy for CGD (Chronic Granulomatous Disease), a rare genetic defect that leaves patients susceptible, often with fatal results, to a common fungus called aspergillus is in its early stages and has enrolled its first patient. Mary Dinaneur, M.D., Ph.D., previously developed a mouse that has the same defect and successfully cured the mouse with gene therapy. Now the Center for Molecular Hematology is supporting gene therapy trials for to attempt to cure CGD in humans.

Two additional molecular hematology clinical trials are already planned. One directed by James Croop, M.D. seeks to correct a rare genetic blood disorder of children called Fanconi Anemia. In this disease, blood stem cells are defective and the disease can lead to total aplastic anemia if untreated.

The other upcoming trial, directed by Franklin Smith, M.D. will continue his work on ex-vivo cord blood expansion for patients with leukemia and various cancers. (See sidebar) In this gene therapy trial, cord blood stem cells, which have been expanded in the laboratory, will be tracked to see if they are able to produce new red and white blood cells in the human body. If they can, this may decrease the amount of scarce donated bone marrow needed by patients for transplantation.

Edward Srour, Ph.D., is co- director of the new Core Center of Excellence for Molecular Hematology at IUSM.

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