Gene, Immune, & Stem Cell Therapy

Quicklinks Emerging Initiatives Research Focus Accomplishments Members

Director:  Donald Kohn, M.D.

Emerging Initiatives

Research Focus

The Gene, Immune and Stem Cell Therapy Program (GISCT) includes scientists and physicians from the Divisions of:

• Bone Marrow Transplant (BMT)/Research Immunology
• Allergy/Clinical Immunology
• Hematology-Oncology 
• Transplant Immunology

The clinical programs of these Divisions provide medical care for children with blood cell disorders, such as sickle cell disease and leukemia, and immune deficiencies, such as Severe Combined Immunodeficiency (SCID) and Acquired Immunodeficiency Syndrome (AIDS).  The grounding provided by interacting with these patients and their families serves as a continued motivation to work to advance medical knowledge and develop new therapies.

The central focus of the GISCT Program is to perform research on the mechanisms and treatment of blood cell diseases and immune disorders. The research of the GISCT is performed at the basic level in the laboratory and at the clinical level in the Hematology, Immunology/Allergy and BMT programs, with a major emphasis on translating new basic findings into new clinical therapies. The nine basic research laboratories of the GISCT focus on stem cell biology, immunology and gene therapy. The clinical research involves performing clinical trials in the setting of bone marrow transplantation and clinical immunology and hematology. Thus, scientists with expertise in these three interrelated scientific areas are collaborating to develop new treatments for diseases of blood cells and the immune system, using cellular and gene therapy methods.

Accomplishments

Hematopoietic Stem Cells
Principal Investigator: Dr. Gay Crooks
Dr. Crooks and her team have been studying the stem cells in bone marrow and cord blood for over ten years. Her group is internationally known for having developed novel ways to identify and characterize these stem cells and "progenitors" that form blood. Building on their expertise in bone marrow stem cells, the Crooks’ team has turned their attention in the past three years to studying the unexpected potential of bone marrow to form the tissues of the pancreas. This research is exciting in its possibilities for the treatment of at least two serious and common diseases that affect the pancreas. Type I Diabetes is caused by complete destruction of the "beta" cells in the pancreas that produce insulin. The high blood sugars that result from a lack of insulin can cause the extensive organ damage seen in Diabetics. Cystic fibrosis is an inherited disease that causes damage to the lungs and the pancreatic ducts and results in early death. In groundbreaking experiments, Dr. Crooks has recently found that bone marrow transplanted into newborn mice can generate both beta cells and ducts in the pancreas. This work may open up important new therapies for these and other diseases based on bone marrow transplantation. Dr. Crooks has been awarded a research grant from the NIH to study this approach in collaboration with Dr. Anil Bhushan, an expert in pancreatic development and member of the Developmental Biology Program.

Bone Marrow Transplantation for Severe Combined Immunodeficiency Diseases
Principal Invetigator:  Kenneth Weinberg, MD
Kenneth Weinberg, MD has developed a new clinical research protocol entitled "Phase I and II Trial of haplo-identical Peripheral Blood Stem Cell Transplant (HSCT) for Severe Combined Immune Deficiency (SCID) with a Campath and Busulfan conditioning regimen. This study is intended to develop safer and more effective methods for stem cell transplants for patients with immune deficiencies. This protocol on haplo-identical HSCT for SCID patients is forming the basis for an NIH RO1 application by Dr. Weinberg, to be submitted this year. This proposal will be a multi-institution study, based at Childrens Hospital Los Angeles. The Pediatric BMT programs at Boston Childrens Hospital, the University of Minnesota, and Childrens Hospital of Philadelphia will enroll SCID infants on this protocol, with data management performed at Childrens Hospital Los Angeles.

Mechanisms of Cell Entry by RNA Viruses
Principal Investigator:  Dr. Paula Cannon
Dr. Cannon’s research is focused on understanding how enveloped RNA viruses enter cells. This has importance for improving gene delivery to cells through retroviral and lentiviral vectors. She is now also using this expertise to study the arenaviruses, a group of human pathogens with the potential to be developed as agents of bioterrorism. She been awarded a grant in the field of Bio-Defense from NIH to study this process. (Aguilar et al, 2003)

Pediatric AIDS
Over the past year, nine HIV-AIDS Clinical Studies involving 103 patients were ongoing. Three of these were conducted as a subsite of the Pediatric AIDS Clinical Trials Group; two were done in collaboration with Pharmaceutical companies; and four were investigator initiated. In collaboration with investigators in the Bone and Body Composition Research Initiative, bone composition was measured in 58 HIV+ subjects. Using the newer technique of quantitative CT, we found that HIV+ children are a quartile smaller than normal controls, but bone composition in the subjects is remarkably preserved. With investigators at UCLA, we continue to study the effects of HIV infection on thymopoiesis. In an ongoing study of varicella vaccine immunization, this live attenuated vaccine appears to be safe and immunogenic in HIV+ children with reasonable preserved immune functions.

Gene Therapy for Beta-thalassemia
Principal Investigator:  Dr. Malik
Dr. Malik and her colleagues have performed exciting and novel studies on gene therapy for beta-thalassemia. (Perelman et al, 2003; Luck et al, 2004) They have developed a cell culture model to study the pathogenic defects of beta-thalassemia by growing bone marrow stem cells from patients under conditions that produce pure populations of red blood cells. In this system, bone marrow from patients with beta-thalassemia fail to produce significant numbers of red blood cells, recreating the defects seen in these patients. Geetha Puthenveetil, a Hematology-Oncology fellow working in Dr, Malik’s lab has performed transfer of a normal human beta-globin gene with a lentiviral vector they developed into the bone marrow stem cells from patients with beta-thalassemia. They showed that this restores the ability of the stem cells to make red blood cells, essentially identically to normal bone marrow. This work represents a major step toward the development of gene therapy for these blood diseases.

Inhibition of HIV-1 Replication by Gene Therapy:  Clinical Trial
Principal Investigators:  Dr. Donald Kohn and Dr. Joseph Church
Drs. Kohn & Church’s groups have a paper in press in Molecular Therapy that describes results from a clinical trial of gene therapy for children with HIV-1 infection. They report results from two children treated by harvesting their bone marrow, isolating the CD34+ stem cells, transducing them to express a gene that inhibits HIV-1 replication, and then re-transplanting them into patients. The procedure proved feasible and safe and there was some engraftment of the gene-modified marrow stem cells. In one subject, a serendipitous finding was made. Anti-HIV-1 medications were halted for a two-month period for medical reasons. During this time, the level of HIV-1 in the blood increased almost 100-fold. Concomitantly, the patient showed an increase in the level of blood T cells that carried the gene that blocks HIV-1, suggesting that it was protecting these cells from being killed by the HIV-1. This study provides proof-of-principle for this approach and will form the basis for the next trial that will use a lentiviral vector for more effective gene transfer.

Faculty Recruitment

• Carolyn Lutzko, PhD was recruited as a scientist in the GISCT and the Division of Research Immunology/BMT.  Dr. Lutzko’s research centers around stem cells, including hematopoietic stem cells, embryonic stem cells and pulmonary stem cells. Carolyn already has NIH funding, from an R21 award she received this past year. 
• Peck Y. Ong, M.D., from the National Jewish Medical Center.
  

Clinical Trials in Gene Therapy
Seminal studies of gene therapy for immune deficiencies have been re-started. Drs. Kohn and Weinberg remain at the forefront of international efforts to develop methods of gene therapy for SCID and AIDS.

Faculty Award
Gay M. Crooks, MD was appointed as a Stohlman Scholar of the Leukemia and Lymphoma Society. This honor recognizes Dr. Crooks’ important contributions to the fields of hematology and stem cell biology, Her studies characterizing the normal stages by which stem cells develop into mature lymphocytes have important implications for understanding the processes by which leukemia develops and how it may be treated. She will be giving a lecture about her research and chairing a scientific session at the upcoming national meeting of the Leukemia and Lymphoma Society.

New Funding
Drs. Parkman and Kapoor have received new grant funding this year for that development of improved methods for hematopoietic stem cell transplantation. Specifically, the focus is on the performance of innovative clinical trials to improve immune reconstitution after stem cell transplantation. This multi-center Program will involve clinical research (led at Childrens Hospital Los Angeles by Dr. Kapoor) with enrollment of BMT patients into research studies, as well as direction of a Core on Assessment of Immune Reconstitution (led by Dr. Parkman) that will analyze samples from all five clinical sites. The existence of our clinical research infrastructure was essential for Drs. Parkman and Kapoor being able to participate in this application and win this award.

Members