Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood
AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses a significant challenge for the durability and safety of AAV-mediated gene therapy. Here, we characterize the innate immune response to AAV in human...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.999021/full |
| _version_ | 1797995136466026496 |
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| author | Corinne J. Smith Nikki Ross Ali Kamal Kevin Y. Kim Elizabeth Kropf Pascal Deschatelets Cedric Francois William J. Quinn Inderpal Singh Anna Majowicz Federico Mingozzi Klaudia Kuranda |
| author_facet | Corinne J. Smith Nikki Ross Ali Kamal Kevin Y. Kim Elizabeth Kropf Pascal Deschatelets Cedric Francois William J. Quinn Inderpal Singh Anna Majowicz Federico Mingozzi Klaudia Kuranda |
| author_sort | Corinne J. Smith |
| collection | DOAJ |
| description | AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses a significant challenge for the durability and safety of AAV-mediated gene therapy. Here, we characterize the innate immune response to AAV in human whole blood. We identified neutrophils, monocyte-related dendritic cells, and monocytes as the most prevalent cell subsets able to internalize AAV particles, while conventional dendritic cells were the most activated in terms of the CD86 co-stimulatory molecule upregulation. Although low titers (≤1:10) of AAV neutralizing antibodies (NAb) in blood did not have profound effects on the innate immune response to AAV, higher NAb titers (≥1:100) significantly increased pro-inflammatory cytokine/chemokine secretion, vector uptake by antigen presenting cells (APCs) and complement activation. Interestingly, both full and empty viral particles were equally potent in inducing complement activation and cytokine secretion. By using a compstatin-based C3 and C3b inhibitor, APL-9, we demonstrated that complement pathway inhibition lowered CD86 levels on APCs, AAV uptake, and cytokine/chemokine secretion in response to AAV. Together these results suggest that the pre-existing humoral immunity to AAV may contribute to trigger adverse immune responses observed in AAV-based gene therapy, and that blockade of complement pathway may warrant further investigation as a potential strategy for decreasing immunogenicity of AAV-based therapeutics. |
| first_indexed | 2024-04-11T09:56:41Z |
| format | Article |
| id | doaj.art-d9b0d374702f4585b36b080c36e4089e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T09:56:41Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d9b0d374702f4585b36b080c36e4089e2022-12-22T04:30:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.999021999021Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human bloodCorinne J. Smith0Nikki Ross1Ali Kamal2Kevin Y. Kim3Elizabeth Kropf4Pascal Deschatelets5Cedric Francois6William J. Quinn7Inderpal Singh8Anna Majowicz9Federico Mingozzi10Klaudia Kuranda11Immunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesResearch Department, Apellis Pharmaceuticals, Waltham, MA, United StatesResearch Department, Apellis Pharmaceuticals, Waltham, MA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesImmunology Department, Spark Therapeutics, Inc., Philadelphia, PA, United StatesAAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses a significant challenge for the durability and safety of AAV-mediated gene therapy. Here, we characterize the innate immune response to AAV in human whole blood. We identified neutrophils, monocyte-related dendritic cells, and monocytes as the most prevalent cell subsets able to internalize AAV particles, while conventional dendritic cells were the most activated in terms of the CD86 co-stimulatory molecule upregulation. Although low titers (≤1:10) of AAV neutralizing antibodies (NAb) in blood did not have profound effects on the innate immune response to AAV, higher NAb titers (≥1:100) significantly increased pro-inflammatory cytokine/chemokine secretion, vector uptake by antigen presenting cells (APCs) and complement activation. Interestingly, both full and empty viral particles were equally potent in inducing complement activation and cytokine secretion. By using a compstatin-based C3 and C3b inhibitor, APL-9, we demonstrated that complement pathway inhibition lowered CD86 levels on APCs, AAV uptake, and cytokine/chemokine secretion in response to AAV. Together these results suggest that the pre-existing humoral immunity to AAV may contribute to trigger adverse immune responses observed in AAV-based gene therapy, and that blockade of complement pathway may warrant further investigation as a potential strategy for decreasing immunogenicity of AAV-based therapeutics.https://www.frontiersin.org/articles/10.3389/fimmu.2022.999021/fullAAVcomplementneutralizing antibodiesinnate immunitygene therapy |
| spellingShingle | Corinne J. Smith Nikki Ross Ali Kamal Kevin Y. Kim Elizabeth Kropf Pascal Deschatelets Cedric Francois William J. Quinn Inderpal Singh Anna Majowicz Federico Mingozzi Klaudia Kuranda Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood Frontiers in Immunology AAV complement neutralizing antibodies innate immunity gene therapy |
| title | Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood |
| title_full | Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood |
| title_fullStr | Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood |
| title_full_unstemmed | Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood |
| title_short | Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood |
| title_sort | pre existing humoral immunity and complement pathway contribute to immunogenicity of adeno associated virus aav vector in human blood |
| topic | AAV complement neutralizing antibodies innate immunity gene therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.999021/full |
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