Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B-Reference-Cited by-同舟云学术

Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B

Published:2011-11-18 Issue:21 Volume:118 Page:5-5
ISSN:0006-4971
Container-title:Blood
language:en
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Author:

Nathwani Amit C¹,Tuddenham Edward GD¹,Rangarajan Savita²,Rosales Cecilia³,McIntosh Jenny H³,Linch David C³,Chowdary Pratima¹,Griffioen Anja¹,Riddell Anne¹,Pie Jun¹,Harrington Chris¹,O’Beirne James⁴,Smith Keith⁵,Pasi John⁶,Glader Bertil⁷,Rustagi Pradip⁸,Ng Catherine⁹,Kay Mark⁸,Zhou Junfang⁹,Spence Yunyu¹⁰,Morton Christopher¹⁰,Allay James¹¹,Coleman John¹¹,Sleep Susan¹¹,Cunningham John M¹²,Basner-Tschakarjan Etiena¹³,Mingozzi Federico¹³,High Katherine A.¹⁴,Gray John T.¹⁰,Reiss Ulrike M.¹⁰,Nienhuis Arthur W.¹⁰,Davidoff Andrew⁹

Affiliation:

1. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London, United Kingdom,

2. Basingstoke and North Hampshire Foundation Trust, Basingstoke, United Kingdom,

3. Department of Haematology, UCL Cancer Institute, London, United Kingdom,

4. Liver Unit, Royal Free NHS Trust, London, United Kingdom,

5. National Health Services Blood and Transplant, United Kingdom,

6. Barts and The London School of Medicine and Dentistry, London, United Kingdom,

7. Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA,

8. Stanford University School of Medicine, Stanford, CA, USA,

9. Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA,

10. Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, USA,

11. Children’s GMP, LLC, St Jude Children’s Research Hospital, Memphis, TN, USA,

12. Department of Pediatrics, University of Chicago, Chicago, USA,

13. Pediatrics - Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA,

14. Howard Hughes Medical Institute, Philadelphia, PA, USA

Abstract

Abstract Abstract 5 Background: Hemophilia B (HB), an X-linked bleeding disorder, is ideally suited for gene therapy. We investigated a novel approach using peripheral vein infusion of a single dose of a serotype-8 pseudotyped self-complementary adeno-associated virus (AAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). Methods: Six severe HB subjects (FIX ≤1%) were enrolled sequentially into one of three dose cohorts with two subjects in each group. Vector was administered without immunosuppression. The subjects were followed for 6–16 months post treatment. Results: AAV-mediated expression of FIX at 2–11% of normal was observed in all subjects. Four of the six have discontinued prophylaxis and remain free of spontaneous hemorrhage. The other two have increased the interval between FIX prophylaxes. A high-dose subject developed asymptomatic, transient elevation of serum transaminases associated with detection of AAV8 capsid specific T cells in peripheral blood. The second high-dose subject experienced a slight increase of liver enzymes, of less clear etiology. Treatment of each with a short course of steroids led to rapid normalization of the transaminases and maintenance of FIX levels in the 3–11% range. Conclusion: Peripheral vein administration of scAAV2/8-LP1-hFIXco was well tolerated and resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype. Immune-mediated clearance of AAV-transduced hepatocytes remains a concern but our data suggest that this process may be controlled with a short course of steroids without loss of transgene expression. Hence, our novel approach shows promise for gene therapy of HB and other protein deficiencies. (ClinicalTrials.gov number, NCT00979238) Disclosures: Nathwani: Amsterdam Molecular Therapeutics: Patents & Royalties. Gray:Amsterdam Molecular Therapeutics: Patents & Royalties. Davidoff:Amsterdam Molecular Therapeutics: Patents & Royalties.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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