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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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