Preclinical safety evaluation of AAV2-sFLT01— a gene therapy for age-related macular degeneration
Open accessAbstract
AAV2-sFLT01 is a vector that expresses a modified soluble Flt1 receptor designed to neutralize the proangiogenic activities of vascular endothelial growth factor (VEGF) for treatment of age-related macular degeneration (AMD) via an intravitreal injection. Owing to minimal data available for the intravitreal route of administration for adeno-associated virus (AAV), we initiated a 12-month safety study of AAV2-sFLT01 administered intravitreally at doses of 2.4 × 10(9) vector genomes (vg) and 2.4 × 10(10) vg to cynomolgus monkeys. Expression of sFlt01 protein peaked at ~1-month postadministration and remained relatively constant for the remainder of the study. Electroretinograms, fluorescein angiograms, and tonometry were assessed every 3 months, with no test article-related findings observed in any group. Indirect ophthalmoscopy and slit lamp exams performed monthly revealed a mild to moderate but self-resolving vitreal inflammation in the high-dose group only, which follow-up studies suggest was directed against the AAV2 capsid. Histological evaluation revealed no structural changes in any part of the eye and occasional inflammatory cells in the trabecular meshwork, vitreous and retina in the high-dose group. Biodistribution analysis in rats and monkeys found only trace amounts of vector outside the injected eye. In summary, these studies found AAV2-sFLT01 to be well-tolerated, localized, and capable of long-term expression.
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AAVs have been shown to elicit immune responses.
“Despite the advantages and promising results from preclinical and clinical trials, AAVs have been shown to elicit immune responses (MacLachlan et al., 2011; Russell et al., 2017), and these responses can limit efficient gene transduction (Korpela et al., 2022).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as MacLachlan et al., 2011
In previous studies, vector sequences have been detected in the brain and optic nerve after AAV2 IVT injection in rats, dogs, mice, and nonhuman primates.
“In previous studies, vector sequences have been detected in the brain and optic nerve after AAV2 IVT injection in rats, dogs (Provost et al., 2005), mice (Griffey et al., 2005), and nonhuman primates (MacLachlan et al., 2011; Calkins et al., 2021).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as MacLachlan et al., 2011
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- Authors
- MacLachlan, T. K., Lukason, M., Collins, M., Munger, R., Isenberger, E., Rogers, C., Malatos, S., DuFresne, E., Morris, J., Calcedo, R., Veres, G., Scaria, A., Andrews, L., & Wadsworth, S.
- Affiliations
- Charles River Laboratories (United States) (US)
- Infinity Vision Dallas (US)
- University of Pennsylvania (US)
- Applied Genetic Technologies (United States) (US)
- Corresponding author
- Wadsworth, Samuel
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 19
- Issue
- 2
- Pages
- 326-334
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3034852
- OpenAlex
- W2084327025
- Cited by
- 166
- References
- 27
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 15 · 2020: 14 · 2019: 11 · 2018: 8 · 2017: 20 · 2016: 9 · 2015: 21 · 2014: 12 · 2013: 7 · 2012: 11
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- age-related macular degeneration, gene therapy, VEGF neutralization, intravitreal injection, adeno-associated virus vectors, preclinical safety, Macaca fascicularis, vector biodistribution
- MeSH terms
- Dependovirus, Animals, Genetic Vectors, Macaca fascicularis, Macular Degeneration, Genetic Therapy, Polymerase Chain Reaction, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor A, Mice
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