Long-term correction of canine hemophilia b by gene transfer of blood coagulation factor ix mediated by adeno-associated viral vector

ABSTRACT HEMOPHILIA B IS A SEVERE X-LINKED BLEEDING DIATHESIS CAUSED BY THE ABSENCE OF FUNCTIONAL BLOOD COAGULATION FACTOR IX, AND IS AN EXCELLENT CANDIDATE FOR TREATMENT OF A GENETIC

DISEASE BY GENE THERAPY. USING AN ADENO-ASSOCIATED VIRAL VECTOR, WE DEMONSTRATE SUSTAINED EXPRESSION (>17 MONTHS) OF FACTOR IX IN A LARGE-ANIMAL MODEL AT LEVELS THAT WOULD HAVE A

THERAPEUTIC EFFECT IN HUMANS (UP TO 70 NG/ML, ADEQUATE TO ACHIEVE PHENOTYPIC CORRECTION, IN AN ANIMAL INJECTED WITH 8.5 × 10 12 VECTOR PARTICLES/KG). THE FIVE HEMOPHILIA B DOGS TREATED

SHOWED STABLE, VECTOR DOSE-DEPENDENT PARTIAL CORRECTION OF THE WHOLE BLOOD CLOTTING TIME AND, AT HIGHER DOSES, OF THE ACTIVATED PARTIAL THROMBOPLASTIN TIME. IN CONTRAST TO OTHER VIRAL GENE

DELIVERY SYSTEMS, THIS MINIMALLY INVASIVE PROCEDURE, CONSISTING OF A SERIES OF PERCUTANEOUS INTRAMUSCULAR INJECTIONS AT A SINGLE TIMEPOINT, WAS NOT ASSOCIATED WITH LOCAL OR SYSTEMIC

TOXICITY. EFFICIENT GENE TRANSFER TO MUSCLE WAS SHOWN BY IMMUNOFLUORESCENCE STAINING AND DNA ANALYSIS OF BIOPSIED TISSUE. IMMUNE RESPONSES AGAINST FACTOR IX WERE EITHER ABSENT OR TRANSIENT.

THESE DATA PROVIDE STRONG SUPPORT FOR THE FEASIBILITY OF THE APPROACH FOR THERAPY OF HUMAN SUBJECTS. Access through your institution Buy or subscribe This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A LONG-TERM STUDY OF AAV GENE THERAPY IN

DOGS WITH HEMOPHILIA A IDENTIFIES CLONAL EXPANSIONS OF TRANSDUCED LIVER CELLS Article 16 November 2020 LIVER-DIRECTED LENTIVIRAL GENE THERAPY CORRECTS HEMOPHILIA A MICE AND ACHIEVES

NORMAL-RANGE FACTOR VIII ACTIVITY IN NON-HUMAN PRIMATES Article Open access 04 May 2022 PRE-CLINICAL EVALUATION OF AN ENHANCED-FUNCTION FACTOR VIII VARIANT FOR DURABLE HEMOPHILIA A GENE

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Harbor, New York,1989). Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank Acuson for supplying the ultrasound equipment, M. Haskins for making the normal dog experiment

possible, and J.H. Liu, S.J. Tai, and M.L. McCleland, as well as the Cell Morphology Core of the Institute for Human Gene Therapy at the University of Pennsylvania, for technical assistance.

We also acknowledge the work of the staff at the vector production facility at Avigen, and the staff of the Francis Owen Blood Research Laboratory at the University of North Carolina-Chapel

Hill. This work was supported by National Institutes of Health Grants R01 HL53668 and P50 HL54500 to K.A.H., and Avigen, a company in which K.A.H. holds equity. P.A.F. is supported by the

Katherine Dormandy Trust for Hemophilia, and J.H.H. was supported by NIH grant F32 HL09397 AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Departments of Pediatrics and Pathology, University

of Pennsylvania Medical Center and The Children's Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA Roland W. Herzog, J. Nathan Hagstrom, Paul A. Fields & Katherine

A. High * Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA Edmund Y. Yang * Avigen Inc., 1201 Harbor Bay Parkway #1000, Alameda,

94502, California, USA Linda B. Couto, Melissa Burton, Gregory M. Podsakoff & Gary J. Kurtzman * Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel

Hill, Chapel Hill, 27599, North Carolina, USA Dan Elwell, Dwight A. Bellinger, Marjorie S. Read, Kenneth M. Brinkhous & Timothy C. Nichols * Institute for Human Gene Therapy, University

of Pennsylvania , Philadelphia, 19104, Pennsylvania, USA Katherine A. High Authors * Roland W. Herzog View author publications You can also search for this author inPubMed Google Scholar *

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this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Katherine A. High. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Herzog, R.,

Yang, E., Couto, L. _et al._ Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. _Nat Med_ 5, 56–63

(1999). https://doi.org/10.1038/4743 Download citation * Received: 17 September 1998 * Accepted: 30 November 1998 * Issue Date: January 1999 * DOI: https://doi.org/10.1038/4743 SHARE THIS

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