Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.
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 x 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 approximately 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.
The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA.
Catherine S
CS
Manno
Glenn F
GF
Pierce
Valder R
VR
Arruda
Bertil
B
Glader
Margaret
M
Ragni
John J
JJ
Rasko
John
J
Rasko
Margareth C
MC
Ozelo
Keith
K
Hoots
Philip
P
Blatt
Barbara
B
Konkle
Michael
M
Dake
Robin
R
Kaye
Mahmood
M
Razavi
Albert
A
Zajko
James
J
Zehnder
Pradip K
PK
Rustagi
Hiroyuki
H
Nakai
Amy
A
Chew
Debra
D
Leonard
J Fraser
JF
Wright
Ruth R
RR
Lessard
Jürg M
JM
Sommer
Michael
M
Tigges
Denise
D
Sabatino
Alvin
A
Luk
Haiyan
H
Jiang
Federico
F
Mingozzi
Linda
L
Couto
Hildegund C
HC
Ertl
Katherine A
KA
High
Mark A
MA
Kay
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000235:genetics; D005164:Factor IX / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007438:Introns / Q000235:genetics; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D014161:Transduction, Genetic
D007371:Interferon-gamma; D005164:Factor IX