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Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , |
| In: | Blood, 97, 2001, 12, S. 3733-3737 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| author_facet |
Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. |
|---|---|
| author |
Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. |
| spellingShingle |
Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. Blood Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX Cell Biology Hematology Immunology Biochemistry |
| author_sort |
ge, ying |
| spelling |
Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. 1528-0020 0006-4971 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v97.12.3733 <jats:p>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 × 1011 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 × 1010 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.</jats:p> Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX Blood |
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| title |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_unstemmed |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_full |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_fullStr |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_full_unstemmed |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_short |
Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_sort |
factors influencing the development of an anti–factor ix (fix) immune response following administration of adeno-associated virus–fix |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood.v97.12.3733 |
| publishDate |
2001 |
| physical |
3733-3737 |
| description |
<jats:p>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 × 1011 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 × 1010 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.</jats:p> |
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| author | Ge, Ying, Powell, Sandra, Van Roey, Melinda, McArthur, James G. |
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| description | <jats:p>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 × 1011 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 × 1010 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.</jats:p> |
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| imprint_str_mv | American Society of Hematology, 2001 |
| institution | DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1 |
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| spelling | Ge, Ying Powell, Sandra Van Roey, Melinda McArthur, James G. 1528-0020 0006-4971 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v97.12.3733 <jats:p>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 × 1011 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 × 1010 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.</jats:p> Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX Blood |
| spellingShingle | Ge, Ying, Powell, Sandra, Van Roey, Melinda, McArthur, James G., Blood, Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX, Cell Biology, Hematology, Immunology, Biochemistry |
| title | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_full | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_fullStr | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_full_unstemmed | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_short | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| title_sort | factors influencing the development of an anti–factor ix (fix) immune response following administration of adeno-associated virus–fix |
| title_unstemmed | Factors influencing the development of an anti–factor IX (FIX) immune response following administration of adeno-associated virus–FIX |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood.v97.12.3733 |