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Open Access Publications from the University of California

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

  • Author(s): De Ravin, Suk See
  • Wu, Xiaolin
  • Moir, Susan
  • Anaya-O'Brien, Sandra
  • Kwatemaa, Nana
  • Littel, Patricia
  • Theobald, Narda
  • Choi, Uimook
  • Su, Ling
  • Marquesen, Martha
  • Hilligoss, Dianne
  • Lee, Janet
  • Buckner, Clarissa M
  • Zarember, Kol A
  • O'Connor, Geraldine
  • McVicar, Daniel
  • Kuhns, Douglas
  • Throm, Robert E
  • Zhou, Sheng
  • Notarangelo, Luigi D
  • Hanson, I Celine
  • Cowan, Mort J
  • Kang, Elizabeth
  • Hadigan, Coleen
  • Meagher, Michael
  • Gray, John T
  • Sorrentino, Brian P
  • Malech, Harry L
  • Kardava, Lela
  • et al.

X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.

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