This project involves the conduct of diagnostic, natural history assessment and therapeutic clinical trials for inherited immune deficiencies. This project specifically include studies of the diagnostic procedures (including genetic diagnosis), and development of treatment modalities that are alternatives to current standard treatment, such as novel allogeneic transplantation regimen and gene therapy (translation of such treatment modalities that are the subject of companion projects with the same types of patients). Patients with X-linked severe combined immunodeficiency (X-SCID/SCID-X1) caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21 often are treated as infants. We evaluate X-SCID patients who have failed to achieve or maintain immune reconstitution despite prior allogeneic bone marrow transplants. Such patients often have waning immunity near the end of their first decade of life, often associated with immune dysregulation, failure to thrive, malnutrition from gastrointestinal malabsorption, pulmonary dysfunction, chronic sinusitis, chronic norovirus and protein-losing enteropathy. We have an ongoing clinical trial to treat X-SCID patients (beyond infancy) with lentivector gene therapy, which to date, has provided significant clinical benefits. We continue to monitor our patients long term. We also follow patients Chronic Granulomatous Disease, another rare primary immunodeficiency disorder (PID) due to defective phagocyte NADPH oxidase complex. CGD patients have defective circulating blood neutrophils that fail to produce microbicidal hydrogen peroxide, resulting in recurrent life threatening infections and premature mortality. Some of these emerging infections are first diagnosed in CGD patients, for example, geosmithia argillacea as an emerging fungus infection in CGD. In addition to recurrent infections including many kinds of difficult to treat fungus infections, CGD patients often have a variety of autoinflammatory syndromes. In addition, we have also noted a high incidence of actual well-defined autoimmune disorders in CGD such as Crohns disease of the gastrointestinal system, systemic lupus erythematosis, sarcoidosis, IgA nephropathy, anti-phospholipid syndrome, and other syndromes of autoimmunity. We have successfully created iPS cells from all forms of CGD, which provide important models for functional studies and for evaluating treatment approaches. Using X-CGD iPSCs derived from X-CGD and AR-CGD, we demonstrated correction of CGD at the safe harbor site as well as at the constitutive genetic loci using gene editing approaches. Moreover, our group has also recently demonstrated that sufficient number of CD34+ stem cells can be obtained from a small quantity of peripheral blood for reprogramming to generate adequate numbers of iPS cells, providing a great resource for investigators in general. For genome editing using the CRISPR approach, we have focused on gene correction that primarily relies on the homology-directed repair (HDR) pathway, using either a short oligo or recombinant AAV-mediated delivery of donors to target PIDs such as CGD, X-SCID and newly described PIDs. We are also exploring the use of gene-editing enhancers to improve HDR and fitness of gene-edited hematopoietic stem/progenitor cells (HSPC). In collaboration with Dr. Philip Murphy and Dr. David McDermott in the Lab of Molecular Immunity, NIAID, we have also been studying the problems that affect patients with WHIM syndrome noting severe neutopenia, increased incidence of human papilloma related cancers and other problems such as chronic pulmonary disease. Studies are in progress to determine better treatments for this disorder. Study of WHIM also interfaced with our related project that seeks to understand the role of CXCR4 (defective in WHIM) in trafficking of hematopoietic cells, including CD34 stem cells into and out of the bone marrow, and assessing ways for gene correction. While developing novel gene correction approaches, we continue to refine current lentivector-mediated gene therapy used for treating multiple PIDs, including the use of transduction enhancers (LentiBoost and Prostaglandin E2), and hope to apply this modality to treatment of patients with adenosine deaminase deficient SCID as well as Wiskott-Aldrich syndrome. Our hope is in generating a universal platform for providing novel therapeutic modalities for many rare immune-deficient genetic disorders. In addition to long-term gene therapy treatment options for PID patients, we are also exploring short-term cellular therapy options by correction of autologous circulating terminally differentiated cells especially for treatment of infections.
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