The Manton Center for Orphan Disease Research
Yu Nee Lee, PhD
From Molecular Mechanism of RAG1 Mediated Primary Immunodeficiency to Gene Correction
Primary immunodeficiency (PID) include a group of genetic diseases that affect development and function of the immune system. In particular, defects in the RAG genes cause some of the most severe forms of PIDs, with recurrent and severe infections and failure to thrive. Milder forms of the disease may present with autoimmunity and organ damage that dramatically reduce the quality of life and reduce life span. We will use a novel assay to investigate the cellular and molecular bases that account for the variable clinical presentation of RAG deficiency.
Treatment of RAG deficiency is based on bone marrow transplantation, but mortality and long-term complications remain a significant problem. Gene therapy has been successfully used to treat some severe forms of PID, however leukemia has been observed in several patients as the result of insertion of the normal gene in dangerous areas of the genome. We will use cellular models of human RAG1 deficiency to investigate the ability of engineered proteins to specifically target the RAG1 gene and permit correction of the gene error. If successful, this will represent an important step toward the development of a customized therapy for severe forms of PID.