Impact of Heparan Sulfate Binding on Transduction of Retina by Recombinant Adeno-Associated Virus Vectors
Open accessAbstract
Adeno-associated viruses (AAVs) currently are being developed to efficiently transduce the retina following noninvasive, intravitreal (Ivt) injection. However, a major barrier encountered by intravitreally delivered AAVs is the inner limiting membrane (ILM), a basement membrane rich in heparan sulfate (HS) proteoglycan. The goal of this study was to determine the impact of HS binding on retinal transduction by Ivt-delivered AAVs. The heparin affinities of AAV2-based tyrosine-to-phenylalanine (Y-F) and threonine-to-valine (T-V) capsid mutants, designed to avoid proteasomal degradation during cellular trafficking, were established. In addition, the impact of grafting HS binding residues onto AAV1, AAV5, and AAV8(Y733F) as well as ablation of HS binding by AAV2-based vectors on retinal transduction was investigated. Finally, the potential relationship between thermal stability of AAV2-based capsids and Ivt-mediated transduction was explored. The results show that the Y-F and T-V AAV2 capsid mutants bind heparin but with slightly reduced affinity relative to that of AAV2. The grafting of HS binding increased Ivt transduction by AAV1 but not by AAV5 or AAV8(Y733F). The substitution of any canonical HS binding residues ablated Ivt-mediated transduction by AAV2-based vectors. However, these same HS variant vectors displayed efficient retinal transduction when delivered subretinally. Notably, a variant devoid of canonical HS binding residues, AAV2(4pMut)ΔHS, was remarkably efficient at transducing photoreceptors. The disparate AAV phenotypes indicate that HS binding, while critical for AAV2-based vectors, is not the sole determinant for transduction via the Ivt route. Finally, Y-F and T-V mutations alter capsid stability, with a potential relationship existing between stability and improvements in retinal transduction by Ivt injection. IMPORTANCE AAV has emerged as the vector of choice for gene delivery to the retina, with attention focused on developing vectors that can mediate transduction following noninvasive, intravitreal injection. HS binding has been postulated to play a role in intravitreally mediated transduction of retina. Our evaluation of the HS binding of AAV2-based variants and other AAV serotype vectors and the correlation of this property with transduction points to HS affinity as a factor controlling retinal transduction following Ivt delivery. However, HS binding is not the only requirement for improved Ivt-mediated transduction. We show that AAV2-based vectors lacking heparin binding transduce retina by subretinal injection and display a remarkable ability to transduce photoreceptors, indicating that other receptors are involved in this phenotype.
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Attempts to manipulate the ILM to reduce the necessary viral load for effective transduction have not resulted in gene expression in the outer retina.
“There have been attempts to manipulate the ILM to reduce the necessary viral load for effective transduction, including the use of proteases to digest the ILM [244,248,249], electric micro-currents [250], and non-penetrating AAV vectors to saturate heparan binding sites in the vitreous [251]. However, these techniques have not resulted in gene expression in the outer retina.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [248]
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Novel AAV44.9-Based Vectors Display Exceptional Characteristics for Retinal Gene Therapy
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- Authors
- Boye, S. L., Bennett, A., Scalabrino, M. L., McCullough, K. T., Van Vliet, K., Choudhury, S., Ruan, Q., Peterson, J., Agbandje-McKenna, M., & Boye, S. E.
- Affiliations
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, USA
- University of Florida (US)
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2016-04-15
- Volume
- 90
- Issue
- 8
- Pages
- 4215-4231
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC4810560
- OpenAlex
- W2319893601
- Cited by
- 79
- References
- 58
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 3 · 2021: 10 · 2020: 6 · 2019: 14 · 2018: 6 · 2017: 10 · 2016: 6
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness
- HHS | NIH | National Eye Institute (R01EY024280, P30EY021721)
- Foundation Fighting Blindness
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus vectors, heparan sulfate binding, retinal transduction, intravitreal injection, internal limiting membrane, AAV2, AAV1, AAV5, AAV8, photoreceptors, serotype differences, subretinal delivery
- MeSH terms
- Dependovirus, Animals, Capsid, Genetic Vectors, Heparan Sulfate, Humans, Injections, Intravenous, Liver, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, Retina, Transduction, Genetic, Vitreous Body, Reassortant Viruses, Photoreceptor Cells, Vertebrate, Injections, Intraocular, HEK293 Cells
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