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Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.
George, Lindsey A; Sullivan, Spencer K; Giermasz, Adam; Rasko, John E J; Samelson-Jones, Benjamin J; Ducore, Jonathan; Cuker, Adam; Sullivan, Lisa M; Majumdar, Suvankar; Teitel, Jerome; McGuinn, Catherine E; Ragni, Margaret V; Luk, Alvin Y; Hui, Daniel; Wright, J Fraser; Chen, Yifeng; Liu, Yun; Wachtel, Katie; Winters, Angela; Tiefenbacher, Stefan; Arruda, Valder R; van der Loo, Johannes C M; Zelenaia, Olga; Takefman, Daniel; Carr, Marcus E; Couto, Linda B; Anguela, Xavier M; High, Katherine A.
Afiliação
  • George LA; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Sullivan SK; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Giermasz A; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Rasko JEJ; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Samelson-Jones BJ; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Ducore J; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Cuker A; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Sullivan LM; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Majumdar S; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Teitel J; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • McGuinn CE; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Ragni MV; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Luk AY; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Hui D; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Wright JF; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Chen Y; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Liu Y; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Wachtel K; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Winters A; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Tiefenbacher S; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Arruda VR; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • van der Loo JCM; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Zelenaia O; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Takefman D; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Carr ME; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Couto LB; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • Anguela XM; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
  • High KA; From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
N Engl J Med ; 377(23): 2215-2227, 2017 12 07.
Article em En | MEDLINE | ID: mdl-29211678
ABSTRACT

BACKGROUND:

The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia.

METHODS:

We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.

RESULTS:

No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion.

CONCLUSIONS:

We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator IX / Terapia Genética / Hemofilia B / Transgenes / Vetores Genéticos Tipo de estudo: Clinical_trials Limite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator IX / Terapia Genética / Hemofilia B / Transgenes / Vetores Genéticos Tipo de estudo: Clinical_trials Limite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article