Long-term safety and efficacy of factor IX gene therapy in hemophilia B
| العنوان: | Long-term safety and efficacy of factor IX gene therapy in hemophilia B |
|---|---|
| المؤلفون: | Yu-min P Shen, Anne Riddell, Christopher L. Morton, Pratima Chowdary, Arthur W. Nienhuis, Jun Pie, Catherine Y.C. Ng, Michael Recht, Andrew M. Davidoff, Mark A. Kay, Elsa Lheriteau, Kathleen Halka, Amit C. Nathwani, Ulreke M Reiss, Jenny McIntosh, Federico Mingozzi, Junfang Zhou, Nishal Patel, John T. Gray, Deo Kumar Srivastava, James A. Allay, Cecilia Rosales, Edward G. D. Tuddenham, Marco Della Peruta, Deepak Raj, Maria I Cancio, David H. Bevan, Katherine A. High, Savita Rangarajan, Etiena Basner-Tschakarjan |
| المساهمون: | REPSOL, Madrid, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Department of Mathematics [Berkeley], University of California [Berkeley], University of California-University of California, University of Oklahoma (OU), University of Salford, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC) |
| المصدر: | N Engl J Med N Engl J Med, 2014, 371 (21), pp.1994-2004. ⟨10.1056/NEJMoa1407309⟩ |
| بيانات النشر: | HAL CCSD, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | medicine.medical_specialty, Genetic enhancement, Transgene, [SDV]Life Sciences [q-bio], Transfection, Gastroenterology, Hemophilia B, Article, Factor IX, Mice, Internal medicine, medicine, Animals, Humans, Ultrasonics, Vector (molecular biology), Microbubbles, biology, business.industry, General Medicine, Genetic Therapy, Coagulation Factor IX, 3. Good health, Clinical trial, Alipogene tiparvovec, Alanine transaminase, Immunology, biology.protein, business, medicine.drug |
| الوصف: | International audience; BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2x10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (+/-SD) of 5.1+/-1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.). |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::46695521d69671c38a875eba4d96e5ebTest https://hal.archives-ouvertes.fr/hal-02881140Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....46695521d69671c38a875eba4d96e5eb |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |