Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy
Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately res...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12693 |
| _version_ | 1797472584958214144 |
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| author | Matthew Piechnik Paige C. Amendum Kazuki Sawamoto Molly Stapleton Shaukat Khan Nidhi Fnu Victor Álvarez Angelica Maria Herreño Pachon Olivier Danos Joseph T. Bruder Subha Karumuthil-Melethil Shunji Tomatsu |
| author_facet | Matthew Piechnik Paige C. Amendum Kazuki Sawamoto Molly Stapleton Shaukat Khan Nidhi Fnu Victor Álvarez Angelica Maria Herreño Pachon Olivier Danos Joseph T. Bruder Subha Karumuthil-Melethil Shunji Tomatsu |
| author_sort | Matthew Piechnik |
| collection | DOAJ |
| description | Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA. |
| first_indexed | 2024-03-09T20:04:30Z |
| format | Article |
| id | doaj.art-1ad44dfbf6134a6093180066ae8bb01a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:04:30Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1ad44dfbf6134a6093180066ae8bb01a2023-11-24T00:35:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201269310.3390/ijms232012693Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene TherapyMatthew Piechnik0Paige C. Amendum1Kazuki Sawamoto2Molly Stapleton3Shaukat Khan4Nidhi Fnu5Victor Álvarez6Angelica Maria Herreño Pachon7Olivier Danos8Joseph T. Bruder9Subha Karumuthil-Melethil10Shunji Tomatsu11Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USAREGENXBIO Inc., Rockville, MD 20850, USAREGENXBIO Inc., Rockville, MD 20850, USAREGENXBIO Inc., Rockville, MD 20850, USANemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USAAdeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA.https://www.mdpi.com/1422-0067/23/20/12693adeno-associated virusmucopolysaccharidosesimmune response |
| spellingShingle | Matthew Piechnik Paige C. Amendum Kazuki Sawamoto Molly Stapleton Shaukat Khan Nidhi Fnu Victor Álvarez Angelica Maria Herreño Pachon Olivier Danos Joseph T. Bruder Subha Karumuthil-Melethil Shunji Tomatsu Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy International Journal of Molecular Sciences adeno-associated virus mucopolysaccharidoses immune response |
| title | Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy |
| title_full | Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy |
| title_fullStr | Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy |
| title_full_unstemmed | Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy |
| title_short | Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy |
| title_sort | sex difference leads to differential gene expression patterns and therapeutic efficacy in mucopolysaccharidosis iva murine model receiving aav8 gene therapy |
| topic | adeno-associated virus mucopolysaccharidoses immune response |
| url | https://www.mdpi.com/1422-0067/23/20/12693 |
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