Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer

Nat Med. 1998 Jan;4(1):58-64. doi: 10.1038/nm0198-058.

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