Abstract
Janus kinase-3 (JAK3) deficiency has recently been identified as a cause of severe combined immunodeficiency (SCID) in humans. We used a mouse model of Jak3-deficient SCID to test a gene therapy approach for treatment of this disease. Transfer of a Jak3 retroviral vector to repopulating hematopoietic stem cells resulted in increased numbers of T and B lymphocytes, reversal of hypogammaglobulinemia, restoration of T-cell activation upon stimulation with mitogens, and development of an antigen-specific immune response after immunization. Analysis for vector copy number in lymphoid and myeloid populations showed a large in vivo selective advantage for Jak3-expressing lymphoid cells. These results show that gene replacement is a feasible treatment strategy for this disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Agammaglobulinemia / etiology
-
Agammaglobulinemia / therapy
-
Animals
-
Antibody Formation
-
B-Lymphocytes / immunology*
-
Bone Marrow Cells / cytology
-
Bone Marrow Transplantation / methods
-
Gene Transfer Techniques
-
Genetic Therapy / methods*
-
Genetic Vectors
-
Humans
-
Immunoglobulin A / blood
-
Immunoglobulin G / blood
-
Immunoglobulin M / blood
-
Janus Kinase 3
-
Lymphocyte Activation
-
Mice
-
Mice, Inbred C57BL
-
Mice, SCID
-
Polymerase Chain Reaction
-
Protein-Tyrosine Kinases / biosynthesis
-
Protein-Tyrosine Kinases / deficiency*
-
Protein-Tyrosine Kinases / genetics*
-
Retroviridae
-
Severe Combined Immunodeficiency / enzymology
-
Severe Combined Immunodeficiency / immunology*
-
Severe Combined Immunodeficiency / therapy*
-
Spleen / immunology
-
T-Lymphocytes / immunology*
Substances
-
Immunoglobulin A
-
Immunoglobulin G
-
Immunoglobulin M
-
Protein-Tyrosine Kinases
-
JAK3 protein, human
-
Jak3 protein, mouse
-
Janus Kinase 3