Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

Catherine S Manno^1, 2, 15, Glenn F Pierce^3, 15, Valder R Arruda^1, 2, 15, Bertil Glader^4, 15, Margaret Ragni⁵, John J E Rasko⁶, Margareth C Ozelo⁷, Keith Hoots⁸, Philip Blatt⁹, Barbara Konkle¹⁰, Michael Dake⁴, Robin Kaye^1, 2, Mahmood Razavi⁴, Albert Zajko¹⁰, James Zehnder⁴, Pradip Rustagi ¹¹, Hiroyuki Nakai⁴, Amy Chew^1, 3, Debra Leonard^2, 12, J Fraser Wright³, Ruth R Lessard³, Jürg M Sommer³, Michael Tigges³, Denise Sabatino¹, Alvin Luk³, Haiyan Jiang³, Federico Mingozzi¹, Linda Couto³, Hildegund C Ertl^1, 13, Katherine A High^1, 2, 14 & Mark A Kay⁴

¹  The Children's Hospital of Philadelphia, and

²  University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.

³  Avigen, Inc., 1301 Harbor Bay Parkway, Alameda, California 94502, USA.

⁴  Stanford University School of Medicine, 300 Pasteur Drive, Room G305, Stanford, California 94305-5208, USA.

⁵  University of Pittsburgh Medical Center, Hemophilia Center of Western Pennsylvania, 3636 Boulevard of the Allies, Pittsburgh, Pennsylvania 15213, USA.

⁶  Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine & Cell Biology, Locked Bag No 6, Newtown NSW 2042, Australia.

⁷  University of Campinas, State University of Campinas, Caixa Postal 6198, CEP, 13083-970, Campinas-Sao Paolo, Brazil.

⁸  University of Texas Houston Health Science Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

⁹  Christiana Care, Christiana Hospital, 4755 Ogletown-Stanton Road, Newark, Delaware 19713, USA.

¹⁰  University of Pennsylvania School of Medicine Presbyterian Medical Center, MAB, Suite 103, 39^th & Market Street, Philadelphia, Pennsylvania 19104, USA.

¹¹  Stanford University, School of Medicine, Department of Hematology, Jane Lathrop Building, 770 Welch Road, Suite 380, Palo Alto, California 94304, USA.

¹²  Weill Medical College of Cornell University, 525 East 68^th Street, New York, New York 10012, USA.

¹³  Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.

¹⁴  Howard Hughes Medical Institute, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.

¹⁵  These authors contributed equally to this work.

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B¹. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 10¹² vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression^*.

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