Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits
The chronic ocular toxicity, tolerability, and inflammation following corneal intrastromal injection of saline or escalating doses of an adeno-associated virus (AAV) containing a codon-optimized α-l-iduronidase (AAV-opt-IDUA) expression cassette were evaluated in New Zealand White rabbits. Corneal o...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120301017 |
| _version_ | 1831704990337466368 |
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| author | Liujiang Song Jacquelyn J. Bower Telmo Llanga Jacklyn H. Salmon Matthew L. Hirsch Brian C. Gilger |
| author_facet | Liujiang Song Jacquelyn J. Bower Telmo Llanga Jacklyn H. Salmon Matthew L. Hirsch Brian C. Gilger |
| author_sort | Liujiang Song |
| collection | DOAJ |
| description | The chronic ocular toxicity, tolerability, and inflammation following corneal intrastromal injection of saline or escalating doses of an adeno-associated virus (AAV) containing a codon-optimized α-l-iduronidase (AAV-opt-IDUA) expression cassette were evaluated in New Zealand White rabbits. Corneal opacity following corneal intrastromal injection resolved by 24 h. Mild elevation of clinical ocular inflammation was observed 24 h after injection, but it returned to baseline by day 7 and no abnormalities were noted through 6 months of observation after injection. Vector genomes and IDUA cDNA were detected in the injected corneas in a dose-dependent manner. Both the lowest administered AAV-opt-IDUA dose, shown to be effective in mucopolysaccharidosis type I (MPS I) dogs, and a 10-fold higher dose of AAV-opt-IDUA resulted in no detectable immunologic response or adverse effect in rabbits. Vector genomes outside of the eye were rarely detected following corneal intrastromal injection of AAV-opt-IDUA, and neutralizing antibodies to the AAV capsid were not present at the experimental conclusion. This study, combined with our previous studies in MPS I dogs, suggests that AAV-opt-IDUA corneal gene therapy following corneal intrastromal injection of AAV-opt-IDUA has the potential to prevent and reverse blindness in MPS I patients in a safe and effective manner. |
| first_indexed | 2024-12-20T16:10:51Z |
| format | Article |
| id | doaj.art-e2cdd5cfe5f34b9e86383fe2d4da7c9a |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-20T16:10:51Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-e2cdd5cfe5f34b9e86383fe2d4da7c9a2022-12-21T19:33:59ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-09-01182432Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White RabbitsLiujiang Song0Jacquelyn J. Bower1Telmo Llanga2Jacklyn H. Salmon3Matthew L. Hirsch4Brian C. Gilger5Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA; Department of Pediatrics, Hunan Normal University Medical College, Changsha, Hunan, China; Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USADepartment of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USADepartment of Ophthalmology, University of North Carolina, Chapel Hill, NC, USADepartment of Clinical Sciences, North Carolina State University, Raleigh, NC 28607, USADepartment of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA; Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USADepartment of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA; Department of Clinical Sciences, North Carolina State University, Raleigh, NC 28607, USA; Corresponding author: Brian C. Gilger, Department of Clinical Sciences, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 28607, USA.The chronic ocular toxicity, tolerability, and inflammation following corneal intrastromal injection of saline or escalating doses of an adeno-associated virus (AAV) containing a codon-optimized α-l-iduronidase (AAV-opt-IDUA) expression cassette were evaluated in New Zealand White rabbits. Corneal opacity following corneal intrastromal injection resolved by 24 h. Mild elevation of clinical ocular inflammation was observed 24 h after injection, but it returned to baseline by day 7 and no abnormalities were noted through 6 months of observation after injection. Vector genomes and IDUA cDNA were detected in the injected corneas in a dose-dependent manner. Both the lowest administered AAV-opt-IDUA dose, shown to be effective in mucopolysaccharidosis type I (MPS I) dogs, and a 10-fold higher dose of AAV-opt-IDUA resulted in no detectable immunologic response or adverse effect in rabbits. Vector genomes outside of the eye were rarely detected following corneal intrastromal injection of AAV-opt-IDUA, and neutralizing antibodies to the AAV capsid were not present at the experimental conclusion. This study, combined with our previous studies in MPS I dogs, suggests that AAV-opt-IDUA corneal gene therapy following corneal intrastromal injection of AAV-opt-IDUA has the potential to prevent and reverse blindness in MPS I patients in a safe and effective manner.http://www.sciencedirect.com/science/article/pii/S2329050120301017Adeno-Associated Virus (AAV)Mucopolysaccharidosis (MPS)Gene therapyCorneal diseaseIntrastromal injection |
| spellingShingle | Liujiang Song Jacquelyn J. Bower Telmo Llanga Jacklyn H. Salmon Matthew L. Hirsch Brian C. Gilger Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits Molecular Therapy: Methods & Clinical Development Adeno-Associated Virus (AAV) Mucopolysaccharidosis (MPS) Gene therapy Corneal disease Intrastromal injection |
| title | Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits |
| title_full | Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits |
| title_fullStr | Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits |
| title_full_unstemmed | Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits |
| title_short | Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits |
| title_sort | ocular tolerability and immune response to corneal intrastromal aav idua gene therapy in new zealand white rabbits |
| topic | Adeno-Associated Virus (AAV) Mucopolysaccharidosis (MPS) Gene therapy Corneal disease Intrastromal injection |
| url | http://www.sciencedirect.com/science/article/pii/S2329050120301017 |
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