Gene therapy for SCID
Children with severe combined immune deficiency (SCID) are born lacking an essential gene that allows the immune system to fight infections. Untreated, SCID is fatal, with the children typically dying of overwhelming infection in the first two years of life. Children with SCID can be successfully treated with a bone marrow transplant that replaces the defective immune system cells with new ones. Unfortunately, some children with SCID will not have a suitable donor, and some who do have a transplant will have serious complications. A multi-center international gene therapy study, using a viral vector manufactured at Cincinnati Children’s, takes the child’s own cells and inserts a normal copy of the defective gene into the child’s own cells. With this approach there is no need for a matched donor and no need for chemotherapy, which leads to fewer complications. Lisa Filipovich, MD, is leading the study at Cincinnati Children’s and the first child has been enrolled and treated. We anticipate that gene therapy will become an important treatment option for babies with SCID, and may allow cure for all the children with fewer complications.
Participation in Clinical Trial Consortia Grows
With the acceptance of our application to join the National Cancer Institute-funded Pediatric Brain Tumor Consortium (PBTC), Cincinnati Children’s became the only pediatric cancer program in the US participating in all four selective national early-phase clinical research consortia: the NCI Pediatric Phase I/Pilot Consortium, the NCI New Approaches to Neuroblastoma Consortium, the PBTC, and the Department of Defense-funded Neurofibromatosis Clinical Consortium.
The PBTC is the premiere national multidisciplinary cooperative research group developing new therapies for CNS tumors of childhood. It has a highly competitive application process, which makes Cincinnati Children’s one of only 11 participating centers. In addition, Maryam Fouladi, MD, MSc, Professor of Pediatrics and Medical Director of Neuro-Oncology, has been elected to serve as national chair of the PBTC.
Experimental Hematology and Cancer Biology
Humoral and paracrine signals from the bone marrow hematopoietic microenvironment control blood generating stem cell activity during regenerative hematopoiesis. A group led by Jose Cancelas, MD, PhD, reported in Proceedings of the National Academy of Sciences, USA, that Connexin-43, a molecule involved in cell-cell communications, exerts a protective role and regulates the blood producing progenitor cell reactive oxygen species content through ROS transfer to the bone marrow microenvironment. This effect results in blood stem cell protection during stress hematopoietic regeneration under chemo or radiation therapies.
Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in children undergoing radiation therapy. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Hartmut Geiger, PhD, in collaboration with several other researchers at Cincinnati Children’s, Wisconsin and Arkansas, identified the thrombomodulin (Thbd)-activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation-induced mortality. Reporting in the journal Nature Medicine, they show that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation.
Small molecule targeted therapy has been hindered by an issue of druggability of target molecules. In a study published in Chemistry and Biology, Yi Zheng, PhD, led a group of chemical biologists to devise a novel approach of rational design of chemical compounds that selectively bind to and inhibit RhoA GTPase, a critical cell signal transducer with a globular structure involved in cancer cell proliferation and neuronal disorders. Their discovery suggests that design and search for low affinity binding chemicals tethered by proper linkers may be useful for rational targeting of “undruggable” biological molecules.
The Hematology Division offers state-of-the-art testing for a variety of complex hematological diagnoses. Over the last year, the Sickle Cell Center, in collaboration with Human Genetics, has launched a genetics-based hemoglobinopathy diagnostic service, making Cincinnati Children’s one of only a few centers in the US that offer comprehensive genetic testing for hemoglobinopathies. Our Special Hemostasis Laboratory has expanded our repertoire of diagnostic studies available for the diagnosis and management of children with bleeding and thrombotic disorders. We recently added several new tests for the detailed diagnosis and characterization of Von Willebrand disease, the most common bleeding disorder in children, making us the only facility in the region offering these assays. We have also added several new tests for the evaluation of platelet function abnormalities, making our laboratory one of the few laboratories nationally with the capability to diagnose children with platelet disorders.