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Factors influencing the development of an anti-factor IX (FIX) immune response following administration of adeno-associated virus-FIX.
Blood 2001; 97(12):3733-7Blood

Abstract

The present study sought to determine the impact of the route of administration of an adeno-associated virus (AAV) vector encoding human factor IX (hFIX) on the induction of an immune response against the vector and its xenogenic transgene product, hFIX. Increasing doses of AAV-hFIX were administered by different routes to C57Bl/6 mice, which typically demonstrate significant immune tolerance to hFIX. The route of delivery had a profound impact on serum hFIX levels as well as the induction of an anti-hFIX humoral immune response. At all dose levels tested, delivery of AAV-hFIX by an intramuscular (IM) route induced an antibody response against the human FIX protein and no hFIX was detected in the serum of animals even at doses of 2 x 10(11) DNA viral particles (vp) of AAV-hFIX. This was in stark contrast to the mice that received AAV-hFIX by intraportal vein (IPV) administration. No anti-hFIX inhibitors were observed in any of these mice and therapeutic levels of hFIX were detected in the serum of all mice that received doses of 2 x 10(10) vp AAV-hFIX and higher. When pre-existing neutralizing immunity to AAV was established in mice, AAV-hFIX administration by either the IM or IPV routes did not result in detectable serum hFIX. Although hFIX expression was not observed in mice with pre-existing neutralizing immunity to AAV, an anti-hFIX response was induced in all of the animals that received AAV-hFIX by the IM route. This was not observed in the preimmune mice that received AAV-hFIX by IPV administration. These results suggest that the threshold of inducing an immune response against a secreted transgene product, in this case the xenoprotein hFIX, is lower when the vector is administered by the IM route even in animals with pre-existing immunity to AAV. (Blood. 2001;97:3733-3737)

Authors+Show Affiliations

Cell Genesys, Dept of Preclinical Biology and Immunology, 342 Lakeside Dr., Foster City, CA 94404, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11389010

Citation

Ge, Y, et al. "Factors Influencing the Development of an Anti-factor IX (FIX) Immune Response Following Administration of Adeno-associated Virus-FIX." Blood, vol. 97, no. 12, 2001, pp. 3733-7.
Ge Y, Powell S, Van Roey M, et al. Factors influencing the development of an anti-factor IX (FIX) immune response following administration of adeno-associated virus-FIX. Blood. 2001;97(12):3733-7.
Ge, Y., Powell, S., Van Roey, M., & McArthur, J. G. (2001). Factors influencing the development of an anti-factor IX (FIX) immune response following administration of adeno-associated virus-FIX. Blood, 97(12), pp. 3733-7.
Ge Y, et al. Factors Influencing the Development of an Anti-factor IX (FIX) Immune Response Following Administration of Adeno-associated Virus-FIX. Blood. 2001 Jun 15;97(12):3733-7. PubMed PMID: 11389010.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Factors influencing the development of an anti-factor IX (FIX) immune response following administration of adeno-associated virus-FIX. AU - Ge,Y, AU - Powell,S, AU - Van Roey,M, AU - McArthur,J G, PY - 2001/6/5/pubmed PY - 2001/7/13/medline PY - 2001/6/5/entrez SP - 3733 EP - 7 JF - Blood JO - Blood VL - 97 IS - 12 N2 - The present study sought to determine the impact of the route of administration of an adeno-associated virus (AAV) vector encoding human factor IX (hFIX) on the induction of an immune response against the vector and its xenogenic transgene product, hFIX. Increasing doses of AAV-hFIX were administered by different routes to C57Bl/6 mice, which typically demonstrate significant immune tolerance to hFIX. The route of delivery had a profound impact on serum hFIX levels as well as the induction of an anti-hFIX humoral immune response. At all dose levels tested, delivery of AAV-hFIX by an intramuscular (IM) route induced an antibody response against the human FIX protein and no hFIX was detected in the serum of animals even at doses of 2 x 10(11) DNA viral particles (vp) of AAV-hFIX. This was in stark contrast to the mice that received AAV-hFIX by intraportal vein (IPV) administration. No anti-hFIX inhibitors were observed in any of these mice and therapeutic levels of hFIX were detected in the serum of all mice that received doses of 2 x 10(10) vp AAV-hFIX and higher. When pre-existing neutralizing immunity to AAV was established in mice, AAV-hFIX administration by either the IM or IPV routes did not result in detectable serum hFIX. Although hFIX expression was not observed in mice with pre-existing neutralizing immunity to AAV, an anti-hFIX response was induced in all of the animals that received AAV-hFIX by the IM route. This was not observed in the preimmune mice that received AAV-hFIX by IPV administration. These results suggest that the threshold of inducing an immune response against a secreted transgene product, in this case the xenoprotein hFIX, is lower when the vector is administered by the IM route even in animals with pre-existing immunity to AAV. (Blood. 2001;97:3733-3737) SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/11389010/Factors_influencing_the_development_of_an_anti_factor_IX__FIX__immune_response_following_administration_of_adeno_associated_virus_FIX_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11389010 DB - PRIME DP - Unbound Medicine ER -