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

Catherine S. Manno, Valder R. Arruda, Glenn F. Pierce, Bertil Glader, Margaret Ragni, John Rasko, Margareth C. Ozelo, Keith Hoots, Philip Blatt, Barbara Konkle, Michael Dake, Robin Kaye, Mahmood Razavi, Albert Zajko, James Zehnder, Hiroyuki Nakai, Amy Chew, Debra Leonard, J. Fraser Wright, Ruth R. LessardJürg M. Sommer, Michael Tigges, Denise Sabatino, Alvin Luk, Haiyan Jiang, Federico Mingozzi, Linda Couto, Hildegund C. Ertl, Katherine A. High, Mark A. Kay

Research output: Contribution to journalArticle

1206 Citations (Scopus)

Abstract

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 B. 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 × 10 12 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.

Original languageEnglish (US)
Pages (from-to)342-347
Number of pages6
JournalNature Medicine
Volume12
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Fingerprint

Factor IX
Hemophilia A
Liver
Hemophilia B
Hepatocytes
Immunomodulation
Capsid
Hepatic Artery
Therapeutics
Portal Vein
Human engineering
Transaminases
Cellular Immunity
Toxicity
Canidae
Dogs
Antigens

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Manno, C. S., Arruda, V. R., Pierce, G. F., Glader, B., Ragni, M., Rasko, J., ... Kay, M. A. (2006). Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature Medicine, 12(3), 342-347. https://doi.org/10.1038/nm1358

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. / Manno, Catherine S.; Arruda, Valder R.; Pierce, Glenn F.; Glader, Bertil; Ragni, Margaret; Rasko, John; Ozelo, Margareth C.; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J. Fraser; Lessard, Ruth R.; Sommer, Jürg M.; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C.; High, Katherine A.; Kay, Mark A.

In: Nature Medicine, Vol. 12, No. 3, 03.2006, p. 342-347.

Research output: Contribution to journalArticle

Manno, CS, Arruda, VR, Pierce, GF, Glader, B, Ragni, M, Rasko, J, Ozelo, MC, Hoots, K, Blatt, P, Konkle, B, Dake, M, Kaye, R, Razavi, M, Zajko, A, Zehnder, J, Nakai, H, Chew, A, Leonard, D, Wright, JF, Lessard, RR, Sommer, JM, Tigges, M, Sabatino, D, Luk, A, Jiang, H, Mingozzi, F, Couto, L, Ertl, HC, High, KA & Kay, MA 2006, 'Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response', Nature Medicine, vol. 12, no. 3, pp. 342-347. https://doi.org/10.1038/nm1358
Manno, Catherine S. ; Arruda, Valder R. ; Pierce, Glenn F. ; Glader, Bertil ; Ragni, Margaret ; Rasko, John ; Ozelo, Margareth C. ; Hoots, Keith ; Blatt, Philip ; Konkle, Barbara ; Dake, Michael ; Kaye, Robin ; Razavi, Mahmood ; Zajko, Albert ; Zehnder, James ; Nakai, Hiroyuki ; Chew, Amy ; Leonard, Debra ; Wright, J. Fraser ; Lessard, Ruth R. ; Sommer, Jürg M. ; Tigges, Michael ; Sabatino, Denise ; Luk, Alvin ; Jiang, Haiyan ; Mingozzi, Federico ; Couto, Linda ; Ertl, Hildegund C. ; High, Katherine A. ; Kay, Mark A. / Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. In: Nature Medicine. 2006 ; Vol. 12, No. 3. pp. 342-347.
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AU - Dake, Michael

AU - Kaye, Robin

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AU - Leonard, Debra

AU - Wright, J. Fraser

AU - Lessard, Ruth R.

AU - Sommer, Jürg M.

AU - Tigges, Michael

AU - Sabatino, Denise

AU - Luk, Alvin

AU - Jiang, Haiyan

AU - Mingozzi, Federico

AU - Couto, Linda

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AU - Kay, Mark A.

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