Seeing the Future: A Review of Ocular Therapy
Abstract
:1. Background
2. Types of Therapy
2.1. Gene Therapy
2.1.1. Gene Augmentation
2.1.2. Modifier Gene Therapy
2.1.3. Optogenetics
2.1.4. Gene Editing
2.1.5. Gene Silencing
2.1.6. Future Directions
2.2. Antibody Therapy
2.2.1. Single-Target Therapies
2.2.2. Dual-Target Therapies
2.2.3. Future Directions
2.3. Cell Therapy
2.3.1. Limbal Stem Cells (LSCs)
2.3.2. Mesenchymal Stem Cells (MSCs)
2.3.3. Human Embryonic-like Stem Cells (hESCs)
2.3.4. Induced Pluripotent Stem Cells (iPSCs)
2.3.5. Neural Stem Cells (NSCs)
2.3.6. Future Directions
2.4. Prostheses
2.4.1. Retinal Prosthesis
2.4.2. Lens Prosthesis
2.4.3. Keratoprosthesis
2.4.4. Future Directions
3. Mode of Delivery
3.1. Injection Routes
3.1.1. Intravitreal
3.1.2. Subretinal
3.1.3. Suprachoroidal
3.1.4. Future Directions
3.2. Vectors
3.2.1. Adenoviral (Ad) Vectors
3.2.2. Adeno-Associated Viral Vectors (AAVs)
3.2.3. Lentiviral Vectors
3.2.4. Naked Plasmid
3.2.5. Future Directions
3.3. Eye Drops
Future Directions
3.4. Nanoparticles
3.4.1. Nanomaterials
3.4.2. Nanomicelles
3.4.3. Liposomes
3.4.4. Dendrimers
3.4.5. Peptides
3.4.6. Future Directions
3.5. Contact Lenses
Future Directions
3.6. Ocular Implants
Future Directions
4. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Disease | Delivery System | Delivery Location | Clinical Trial Number | FDA-Approved Therapy |
---|---|---|---|---|
Achromatopsia | AAV | Subretinal | NCT03278873, NCT02935517, NCT02599922 | None |
Dry AMD | Retinal prosthesis, Stem cells | Subretinal Intravitreal | NCT03392324, NCT01736059, NCT04339764, NCT04627428, NCT05187104 | None |
Wet AMD | Lentivirus, Monoclonal antibody, AAV, Axitinib suspension, Axitinib implant, Durasert, Soluble protein decoy, Brachytherapy | Subretinal Intravitreal Suprachoroidal Episcleral | NCT01678872, NCT04777201, NCT04832724, NCT05891548, NCT04989699, NCT05381948, NCT04423718, NCT05112861, NCT02988895 | Aflibercept (Eylea), VEGF inhibitor, for intravitreal injection. Faricimab (Vabysmo), VEGF and Ang-2 inhibitor, for intravitreal injection. Ranibizumab (Lucentis, Byooviz), VEGF inhibitor, for intravitreal injection. Brolucizumab (Beovu), VEGF inhibitor, for intravitreal injection. |
Geographic Atrophy Secondary to AMD | Pegcetacoplan (APL-2) C3 inhibitor, Antisense Inhibitor of Complement Factor B, AAV | Intravitreal Subcutaneous Subretinal | NCT04770545, NCT03815825, NCT04656561, NCT06018558 | Pegcetacoplan (Syfovre), C3 inhibitor, for intravitreal injection. Avacincaptad pegol (Izervay), C5 inhibitor, for intravitreal injection. |
Choroideremia | AAV | Intravitreal | NCT04483440 | None |
Diabetic Macular Edema | Triamcinolone acetonide, Ranibizumab, Anti-IL6 monoclonal antibody, Dexamethasone, Bevacizumab, Drug implant, aflibercept | Suprachoroidal Intravitreal Eye drops | NCT05512962, NCT05151744, NCT05066997, NCT05112861, NCT04469595, NCT04411693, NCT04108156, NCT04429503 | Ozurdex biodegradable implant for sustained dexamethasone release. Faricimab (Vabysmo), VEGF and Ang-2 inhibitor, for intravitreal injection. Ranibizumab (Lucentis, Byooviz), VEGF inhibitor, for intravitreal injection. Aflibercept (Eylea), VEGF inhibitor, for intravitreal injection. Brolucizumab (Beovu), VEGF inhibitor, for intravitreal injection. |
Diabetic Retinopathy | Stem cells, Selective integrin inhibitor, Ranibizumab implant, Aflibercept, Brolucizumab | Intravitreal Eye drops | NCT01736059, NCT05409235, NCT04503551, NCT04708145, NCT04278417 | Aflibercept (Eylea), VEGF inhibitor, for intravitreal injection. Ranibizumab (Lucentis, Byooviz), VEGF inhibitor, for intravitreal injection. |
Dry Eye Disease | Lipid conjugated chemerin peptide agonist, Small molecule, siRNA, rhNGF, TRPM8 agonist, synthetic peptide, Thermomechanical system | Eye drops Peri-orbital | NCT05759208, NCT05403827, NCT05310422, NCT05133180, NCT05493111, NCT05136170, NCT05467293, NCT05162261, NCT04795752 | Miebo, Restasis, a cyclosporin drug, and Eysuvis, an ophthalmic suspension with loteprednol etabonate as eye drops. |
Glaucoma | Human retinal pigment epithelium cell therapy, carbonic anhydrase inhibitor, prostaglandin F2 alpha analog, EP2 receptor agonist | Intravitreal Eye drops Peri-orbital | NCT02862938, NCT02390284, NCT05397600, NCT04761705, NCT03850782, NCT03868124, NCT03519386 | Prostaglandins: Latanoprost, Ravoprost, Tafluprost, and Bimatoprost (implant/eye drops) as eye drops. Rho kinase inhibitors: Netarsudil as eye drops. Cholinergic agonists: Pilocarpine as eye drops. Alpha-adrenergic agonists: Apraclonidine and Brimonidine as eye drops. Beta blockers: Timolol as eye drops. Carbonic anhydrase inhibitors: Dorzolamide as eye drops. Omidenepag isopropyl (OMLONTI), EP2 receptor agonist, eye drops. |
Leber Congenital Amaurosis | AAV, RNA antisense oligonucleotide, CRISPR/Cas9 | Subretinal Intravitreal | NCT01208389, NCT03920007, NCT00481546, NCT00999609, NCT03913143, NCT03872479 | AAV2-RPE65 (Luxturna) for subretinal injection gene replacement therapy. |
Leber Hereditary Optic Neuropathy | AAV | Intravitreal | NCT02161380, NCT03293524 | None |
RP | Small molecule, Stem cells, Human retinal progenitor cells, Electrical stimulation, AAV, RNA Antisense oligonucleotide, Retinal prosthesis | Intravitreal Subretinal Trans corneal | NCT05392751, NCT04925687, NCT02086890, NCT02464436, NCT02556736, NCT05285618, NCT04945772, NCT04123626, NCT05158296, NCT01736059, NCT05203939 | Argus II epiretinal Prosthesis System. AAV2-RPE65 (Luxturna) for subretinal injection gene replacement therapy. |
X-linked RP | AAV | Intravitreal | NCT04517149 | AAV2-RPE65 (Luxturna) for subretinal injection gene replacement therapy. |
X-linked Retinoschisis | AAV | Intravitreal | NCT02317887 | None |
Usher Syndrome | Lentivirus, RNA Antisense oligonucleotide | Intravitreal Subretinal | NCT05158296, NCT02065011 | None |
Stargardt Disease | Equine infectious anemia virus, AAV, complement factor C5 inhibitor | Subretinal Intravitreal | NCT01736592, NCT03364153, NCT05956626 | None |
Name | Ocular Tissue Type | Duration | Efficacy | Toxicity |
---|---|---|---|---|
Adeno-associated virus | ||||
AAV1 | Subretinal: RPE [125]. | Expression up to 6 months [125]. | High transduction efficiency in ONL [126]. | Inflammation above 5 × 1010 vg/eye [127]. |
AAV2 | Intravitreal: Retinal ganglion cells, Müller cells, ciliary body, inner nuclear layer (INL). Subretinal: Mainly photoreceptors, also RPE. | Initial expression at 28 days post-injection [128]. Expression continues at 7–8 months post-injection [129]. | Moderate transduction efficiency of photoreceptors and RGCs, low transduction of RPE cells [128]. | Formation of AAV2 antibodies and possible retinal detachment above 8.0 × 1010 vg/eye [130,131]. |
AAV4 | Subretinal: RPE, retina [125]. | Expression up to 6 months [125]. | High transduction efficiency of the ONL [128]. | Inflammation observed above 4.8 × 1010 vg/eye [132]. |
AAV5 | Subretinal: RPE, photoreceptors [125]. | Initial expression starting at 14–21 days post-injection. Expression continues at 7–8 months post-injection [129]. | High transduction efficiency in the retina compared with other AAVs [129]. | Retinal thinning observed above 1.1 × 1012 vg/eye [133]. |
AAV8 | Subretinal: photoreceptors. | Expression up to 6 months [125]. | Low transduction efficiency in the ONL [128]. | Inflammation and anti-AAV8 antibodies above a dose of 1 × 1010 vg/eye [130]. |
AAV9 | Subretinal: Photoreceptors. | Expression up to 6 months [125]. | Moderate transduction efficiency in the ONL [128]. | Immunogenic responses observed at doses above 1 × 1010 vg/eye [134]. |
Adenovirus | ||||
Adenovirus serotype 5 (AdV5) | Subretinal: All retinal layers except ONL, some RPE cells [135]. | Expression begins ~2 weeks post-injection. Expression continues up to 6 months post-injection [136]. | Low due to high prevalence of Ad5 serotypes in humans. | Triggers immune responses starting at 4 × 105 IU/eye [137]. |
Lentiviral vectors | ||||
Lenti-VSVG (lentiviral vectors pseudotyped in a vesicular stomatitis virus glycoprotein envelope) | Intravitreal: INL. Subretinal: RPE, photoreceptors. | Initial expression by 7 days post-injection. Expression continues 4–5 months post-injection [128]. | High transduction efficiency. | Triggers immune response at 1.4 × 107 IU/eye [128]. Derived from virus that can integrate into host genome. |
Lenti–Mokola (Mokola envelope) | Subretinal: RPE. | Initial expression by 7 days. Expression continues at 3 months post-injection [128]. | High transduction efficiency. | Triggers immune response at 6 × 105 IU/eye [128]. Derived from virus that can integrate into host genome. |
Topical | ||||
Eye drops | Cornea, trabecular meshwork. | A few hours. | Low to moderate due to leakage through nasolacrimal system. | Concentration of the preservative, benzalkonium chloride (BAK), should be below 0.0005% to avoid toxicity to eye [138]. |
Nanoparticles | ||||
Nanomicelles | Ocular anterior and poster segments. | Sustained release over several days [11]. | High for delivery of hydrophobic drugs to the cornea and trabecular meshwork. | Concentration should be less than 2 mg/mL [139,140]. |
Liposomes | Cornea, retina (blood–retinal barrier). | Up to 3 months [11]. | High efficacy for corneal and blood–retinal barrier uptake. | Low toxicity up to concentrations of 50 µg/mL [141]. Dependent on addition of chemical groups. |
Dendrimers | Cornea, retina. | A few weeks to a month [11]. | High corneal drug residence time. Can cross blood–retinal barrier depending on polymer chemistry [11]. | Low toxicity at concentrations up to 100 μg/mL [142,143]. Dependent on chemical modifications. |
Devices | ||||
Contact lens | Cornea, conjunctiva, trabecular meshwork. | Immersion in drug: temporary duration. Nanoparticle-loaded: several days. | Moderate drug uptake through the corneal layers [11]. | May cause corneal inflammation [11]. |
Intraocular Implants | Lens, trabecular meshwork, retina. | Sustained release over several months. | High due to intraocular localization. | Low toxicity for many biodegradable implants [11]. |
Retinal prosthesis | Retina. | Permanent electrical stimulation. | Moderate: limited by reduced specificity of cell targets and higher thresholds of inner retinal neurons compared with photoreceptors. | Generally considered biocompatible [90]. |
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Whalen, M.; Akula, M.; McNamee, S.M.; DeAngelis, M.M.; Haider, N.B. Seeing the Future: A Review of Ocular Therapy. Bioengineering 2024, 11, 179. https://doi.org/10.3390/bioengineering11020179
Whalen M, Akula M, McNamee SM, DeAngelis MM, Haider NB. Seeing the Future: A Review of Ocular Therapy. Bioengineering. 2024; 11(2):179. https://doi.org/10.3390/bioengineering11020179
Chicago/Turabian StyleWhalen, Maiya, Monica Akula, Shannon M. McNamee, Margaret M. DeAngelis, and Neena B. Haider. 2024. "Seeing the Future: A Review of Ocular Therapy" Bioengineering 11, no. 2: 179. https://doi.org/10.3390/bioengineering11020179
APA StyleWhalen, M., Akula, M., McNamee, S. M., DeAngelis, M. M., & Haider, N. B. (2024). Seeing the Future: A Review of Ocular Therapy. Bioengineering, 11(2), 179. https://doi.org/10.3390/bioengineering11020179