NHLBI Comprehensive
Sickle Cell Centers

About University of Southern California Comprehensive Sickle Cell Center

The Comprehensive Sickle Cell Center is an inter-disciplinary collaboration of basic and clinical research units at the University of Southern California Keck School of Medicine. This program has been in existence since the late 1950's, initially through the efforts of Darleen Powars, MD and has grown to include an adult program under Cage S. Johnson, MD - the current Center Director and satellite programs at Childrens Hospital Los Angeles under Thomas Coates, MD and Punam Malik, MBBS, MD. The primary location of the Center is at Los Angeles County+USC Medical Center, originally established in 1878. A partial history of the institution has been published in Neurosurgery 56:1162-1163, 2005, and many will recognize "the General Hospital" from the opening scene of the television soap opera of the same name.

The current Center programs include comprehensive care and consultation for children and adults with sickle cell disease, as well as other hemoglobinopathies. Our outreach extends throughout the entire Southern California region. The overall focus and unifying theme of our research has been the pathophysiology, clinical consequences and treatment of vascular events in sickle cell disease. Vascular disorders, including vascular occlusion, represent the most important cause of morbidity and mortality in this disease, yet their pathophysiology is still incompletely understood and their treatment remains largely unsatisfactory. Determining possible genetic bases for the variable clinical severity of the disease and genetic approaches to therapy are also of central interest, yet again our understanding in these areas is incomplete. Our current studies are briefly described in the following section.

An ongoing investigation on the effect of genes outside the globin loci on clinical variability is aimed at determining whether the Lewis blood group phenotype and genotype predicts overall disease severity and is associated with specific end-organ complications of this disease. Preliminary data suggests that the absence of this antigen on the erythrocyte membrane is associated with a higher hospitalization rate compared to those with Le (a+b-) or Le (a-b+) phenotype. Another project is developing a mouse model of the Acute Chest Syndrome in order to study the biochemical and cellular inflammatory responses within the lung; a more precise definition of these intra-pulmonary responses should provide a rationale for the development of improved therapeutic approaches for this complication of the disease. An investigation of gene therapy using the gamma-globin gene to correct the beta-globin sickle defect in autologous hematopoietic stem cells is underway. This project is developing self-inactivating lentiviral vectors that would transduce non-dividing hematopoietic stem cells at high levels, be stably transmitted and produce sustained and therapeutic levels of the human gamma-globin gene as an anti-sickling globin. These vectors will be screened in mouse erythroleukemia cells. Optimized vectors will then studied for their ability to correct sickle cell disease in transgenic sickle mice or in erythrocytes grown in culture from human sickle progenitor cells, using the in vitro model of human erythropoiesis or xenografted immune deficient mice. These data will provide the necessary preclinical studies for taking gene therapy of sickle cell disease to a clinical trial.

Our Center continues to be a strong proponent for developing young investigators under the Sickle Cell Scholar Program. Our current Scholar is investigating the effects of colloidal solutions (e.g., dextrans, starches) on sickle blood flow leading to a decrease in blood viscosity and improved microvascular flow. The objective of the Scholar's project is to design and develop infusible polymeric agents with a sustained circulation time that will improve microvascular blood flow following ischemia. Our projects are supported by a Laboratory Core that provides relevant erythrocyte biophysical, morphological and rheological data, as well as specialized hematological measurements and hemoglobin analyses. In addition, the Laboratory Core conducts experimental studies related to blood rheology and biophysical behavior in sickle cell disease. Current studies underway include: 1) evaluating the "optimum hematocrit" hypothesis for mixtures of AA and SS RBC suspended in sickle plasma; 2) exploring the usefulness of a gel permeation technique as a rapid assay for anti-sickling agents; 3) determining the accuracy and reproducibility of a new automated blood viscometer specifically designed for clinical use.