Abstract
Genetic disorders exhibit variable expressivity and phenotypic heterogeneity. Some are fatal or severely debilitating. Primary immunodeficiency diseases (PIDs) are a heterogeneous group of monogenic disorders caused by defects in genes responsible for different components of the immune system. PIDs have phenotypic heterogeneity with varying degrees of immunodeficiency and immune dysregulation. Patients with PIDs are susceptible to infections. Some have severe symptoms. If early diagnosis and treatment could be provided, the diseases could be cured resulting in improved quality of life. Patients with severe immune deficiency have proved to be cured by stem cell transplantation or gene-based therapy. For example, Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia and eczema. Without bone marrow transplantation, most patients die by 10 years of age due to recurrent infections, haemorrhage or autoimmune diseases. Chronic granulomatous disease (CGD) is a primary immunodeficiency that affects phagocytes of the innate immune system. However, donor availability constrains its usage. Recent technologies including gene therapy and genome editing have been developed and successfully applied to effectively treat some life-threatening genetic disorders in some countries. Very recently, genome editing has proven capable of advancing cell therapies in hemoglobinopathies. For some incurable fatal genetic diseases, development of gene-based therapy would be necessary. The aim of this project is to develop the gene therapy or genome editing platform for primary immunodeficiency diseases systematically both in vitro and in vivo. The safety and efficacy will be evaluated. In this study, WAS-iPSCs, CGD-iPSCs and iPSC-derived HSCs were successfully generated for use as gene editing models. In addition, the causative variant in the WAS gene derived from the patient’s cells were corrected. This study will provide more insight into the use of genome editing that can be applied to the therapeutic modification of human inherited diseases requiring gene correction therapy. In addition, it could lead to the development of effective and reliable protocols for therapies using genome editing strategies in our country in the future.
