Modeling Human Severe Combined Immunodeficiency and Correction by CRISPR/Cas9-Enhanced Gene Targeting

• DOI: 10.1016/j.celrep.2015.08.013
• Publication Date: 2015-08-29T02:43:21Z
• Authors: Chia-Wei Chang; Yi-Shin Lai; Erik Westin; Alireza Khodadadi...; Kevin M. Pawlik; Lawrence S. Lamb; Frederick D. Goldman; Tim M. Townes
• Keywords: Janus kinase 3; Lymphopoiesis

Mutations of the Janus family kinase JAK3 gene cause severe combined immunodeficiency (SCID). deficiency in humans is characterized by absence circulating T cells and natural killer (NK) with normal numbers poorly functioning B (T(-)B(+)NK(-)). Using SCID patient-specific induced pluripotent stem (iPSCs) a cell vitro differentiation system, we demonstrate complete block early development JAK3-deficient cells. Correction mutation CRISPR/Cas9-enhanced targeting restores development, including production mature populations broad receptor (TCR) repertoire. Whole-genome sequencing corrected demonstrates no CRISPR/Cas9 off-target modifications. These studies describe an approach for study human lymphopoiesis provide foundation correction therapy immunodeficiencies.