Suprachoroidal gene transfer with nonviral nanoparticles in large animal eyes

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Abstract

Suprachoroidal nonviral gene therapy with biodegradable poly(β-amino ester) nanoparticles (NPs) provides widespread expression in photoreceptors and retinal pigmented epithelial (RPE) cells and therapeutic benefits in rodents. Here, we show in a human-sized minipig eye that suprachoroidal injection of 50 μl of NPs containing 19.2 μg of GFP expression plasmid caused GFP expression in photoreceptors and RPE throughout the entire eye with no toxicity. Two weeks after injection of 50, 100, or 200 μl, there was considerable within-eye and between-eye variability in expression that was reduced 3 months after injection of 200 μl and markedly reduced after three suprachoroidal injections at different locations around the eye. Reduction of bacterial CpG sequences in the expression plasmid resulted in a trend toward higher expression. These data indicate that nonviral suprachoroidal gene therapy with optimized polymer, expression plasmid, and injection approach has potential for treating photoreceptors throughout the entire retina of a human-sized eye.

Abstract

Widespread photoreceptor transfection in human-sized eyes shows the feasibility of suprachoroidal nonviral gene therapy.

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Most cited references 23

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Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

Stephen Russell, Jean Bennett, Jennifer Wellman … (2017)

Background Phase 1 studies have shown potential benefit of gene replacement in RPE65 -mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. Methods In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5×10 11 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. Findings Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. Interpretation Voretigene neparvovec gene replacement improved functional vision in RPE65 -mediated inherited retinal dystrophy previously medically untreatable. Funding Spark Therapeutics.

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Antioxidants reduce cone cell death in a model of retinitis pigmentosa.

Lili Lu, Geraint B Rogers, Peter A Campochiaro … (2006)

Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit.

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Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa.

Fulton Wong, Jikui Shen, Peter A Campochiaro … (2005)

Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation. Copyright 2005 Wiley-Liss, Inc.

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Author and article information

Contributors

Jikui Shen:

ORCID: https://orcid.org/0000-0002-5262-5606

Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Raquel Lima e Silva:

ORCID: https://orcid.org/0000-0002-4325-5754

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Mingliang Zhang:

ORCID: https://orcid.org/0000-0003-2285-3592

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Kathryn M. Luly:

ORCID: https://orcid.org/0000-0001-9020-9155

Role: InvestigationRole: ResourcesRole: Visualization

Sean F. Hackett: Role: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Stephany Y. Tzeng:

ORCID: https://orcid.org/0000-0002-7561-482X

Role: InvestigationRole: ResourcesRole: ValidationRole: Writing - review & editing

Shirley M. Lowmaster:

ORCID: https://orcid.org/0009-0005-3631-257X

Role: InvestigationRole: Writing - review & editing

Sydney R. Shannon: Role: InvestigationRole: ResourcesRole: VisualizationRole: Writing - review & editing

David R. Wilson:

ORCID: https://orcid.org/0000-0002-8708-4248

Role: MethodologyRole: Resources

Jordan J. Green:

ORCID: https://orcid.org/0000-0003-4176-3808

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Peter A. Campochiaro:

ORCID: https://orcid.org/0000-0003-2531-8229

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: 08 March 2024

Publication date (Electronic, pub): 08 March 2024

Volume: 10

Issue: 10

Electronic Location Identifier: eadl3576

Affiliations

[ ¹ ]Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

[ ² ]Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

[ ³ ]Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

[ ⁴ ]Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.

[ ⁵ ]Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.

[ ⁶ ]Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.

[ ⁷ ]Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

[ ⁸ ]Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Author notes

[* ]Corresponding author. Email: green@ 123456jhu.edu (J.J.G.); pcampo@ 123456jhmi.edu (P.A.C.)

[†]

These authors contributed equally to this work.

Author information

Jikui Shen https://orcid.org/0000-0002-5262-5606

Raquel Lima e Silva https://orcid.org/0000-0002-4325-5754

Mingliang Zhang https://orcid.org/0000-0003-2285-3592

Kathryn M. Luly https://orcid.org/0000-0001-9020-9155

Stephany Y. Tzeng https://orcid.org/0000-0002-7561-482X

Shirley M. Lowmaster https://orcid.org/0009-0005-3631-257X

David R. Wilson https://orcid.org/0000-0002-8708-4248

Jordan J. Green https://orcid.org/0000-0003-4176-3808

Peter A. Campochiaro https://orcid.org/0000-0003-2531-8229

Article

Publisher ID: adl3576

DOI: 10.1126/sciadv.adl3576

PMC ID: 10923522

PubMed ID: 38457512

SO-VID: f7e21826-440c-4d15-a8a5-774106782ff6

Copyright © Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.