The daily impacts of vision impairment due to debilitating retinal diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR), are widespread. These diseases are responsible for acquired vision loss among working adults between the ages of 20 and 74 years and elderly patients older than 60 years of age.¹ Globally, approximately 126.6 million individuals are negatively impacted by DR, and another 187 million by AMD.¹

There are several US Food and Drug Administration (FDA)-approved therapeutics for wet AMD and DR, including ranibizumab and aflibercept. However, due to the short half-lives of these anti-VEGF therapeutics, patients need frequent intravitreal injections for disease control, which leads to high treatment burden.^2,3 There is an unmet need to improve the potency of therapeutics while reducing patient burden through improved drug delivery and sustainability, which is currently being explored via clinical trials.² Ocular gene therapy is an emerging sustained delivery treatment option for patients with retinal diseases.⁴ The suprachoroidal space (SCS), the space between the sclera and choroid, is the proposed injection site for gene therapy, because it has potential to be less invasive while also providing adequate gene expression to control disease. This article reviews the SCS, the viral vectors available for gene therapy, and current clinical trials investigating unique suprachoroidal gene therapy therapeutics.

THE SUPRACHOROIDAL SPACE

The SCS presents as a small pocket between the sclera and choroid of the eye and is being investigated as an injection site for posterior-segment disease therapeutics.⁵ The location of this space with respect to the blood–retinal barrier, the scleral spur, and optic nerve may allow for decreased off-target binding and immune responses to injected therapeutics.^2,5

It has been demonstrated that fluid injected into this space flows posteriorly toward the choroid and RPE, allowing for targeted drug administration.^2,5 Successful treatment of retinal diseases relies on sufficient bioavailability near the retinal pigment epithelium (RPE) tissue.⁵ Thus, suprachoroidal injections may result in increased bioavailability within diseased tissue, reducing therapeutic dosage required to achieve favorable outcomes.

The SCS can be visualized as a hyperreflective band via enhanced-depth imaging optical coherence tomography (EDI-OCT) and swept-source OCT, but it is difficult to view prior to suprachoroidal injection because it is typically collapsed due to intraocular pressure (IOP). Reliable visualization of the SCS is achieved following suprachoroidal injection as the space expands, holding up to 1 mL of fluid.^5-7 Detection rates of SCS can be influenced by age, choroidal thinning from retinal diseases, and choroidal vessel protein leakage into the SCS.^6,7

Access to the SCS via sclerotomy followed by catheter or cannula placement allows for improved visualization and subsequent ease of therapeutic administration within the space.⁸ Treatment administration within the SCS can also be done in a clinic setting using either hypodermic needles or hollow microneedles. Hypodermic needles are readily available and require increased precision and attention to applied force due to limited SCS access.⁵ Microneedles inject medication directly into the SCS without retinal penetration because they contain scleral-length needles.⁵

Favorable phase 3 clinical trial results have demonstrated efficacy and safety of the SCS as an injection site for retinal disease treatment. The recent FDA approval of triamcinolone acetonide injectable suspension as the first medicine delivered via suprachoroidal injection (Xipere; Bausch + Lomb) has shown positive results.⁹ Further clinical studies are required to determine efficacy, safety, and durability of therapeutic administration in the SCS.

GENE THERAPY VECTORS

The eye is an immune-privileged, compartmentalized organ that permits localized medication delivery and is a target for gene therapy. Viral vectors ensure long-term treatment with adequate gene expression, providing an alternative treatment avenue for retinal diseases.⁴ Gene therapy delivery requires one of 3 viral vectors: adeno-associated viruses (AAVs), adenovirus (Ad) vectors, and lentiviral vectors. Determining which viral vector to utilize as a therapeutic mechanism for retinal diseases is based on longevity of gene expression to significantly reduce treatment burden. The goal of gene therapy is to provide a single treatment with minimal risk of immune response.¹⁰

Because they can carry large genomes (4.7 kbp) encapsulated in proteins, AAVs are the most utilized gene therapy delivery mechanism. These vectors reduce the risk of host immune response, but they have the ability to alter the host’s genome.¹¹ AAVs present increased gene expression in nondividing cells, which is significantly more than current anti-VEGF drugs.¹⁰ Gene expression is effectively altered within RPE cells and photoreceptors; thus, serotypes can easily be engineered.¹²

Ad vectors consist of a large genome (~36 kbp) encapsulated in a protein shell.¹³ These vectors are less commonly used in gene therapy because they do not integrate into the host cell’s genome, limiting their expression lifespan.¹¹ Ad vectors also have a higher risk of mild inflammation due to host cell immune responses.¹¹ Additionally, immunogenicity is slightly higher among Ad vectors compared to AAVs.¹⁰

Lentiviral vectors are composed of single-stranded RNA as opposed to DNA like AAVs and Ad vectors.¹¹ These vectors can integrate into the host cell’s genome to ensure longevity of gene expression.⁶ Due to the potential risk of mutagenesis associated with lentiviral vectors, adverse reactions may be increased.⁶

PHASE 2 STUDIES

ALTITUDE, a phase 2 study, is currently evaluating the safety, efficacy, and tolerability of a single dose of NAV AAV8 vector encoding a transgene for anti-VEGF fab in patients with DR without center-involved diabetic macular edema (CI-DME) who suffer from moderate to severe nonproliferative DR (NPDR) or mild proliferative DR (PDR).¹⁴ In this multicenter, open-label, randomized, controlled dose-escalation trial, eyes were placed into 1 of 3 treatment groups: a 3:1 ratio of single dose 2.5 x 10¹¹ genomic copies per eye (GC/eye) with observational control; a 3:1 ratio of a single dose of 5 x 10¹¹ GC/eye with observational control; or a single dose of 5 x 10¹¹ GC/eye in patients positive for neutralizing antibody (NAb).¹⁴

Preliminary data from cohort 1 demonstrate that the single dose of AAV8 vector encoding a transgene for anti-VEGF fab was well tolerated in 15 patients. On the Early Treatment Diabetic Retinopathy Study–Diabetic Retinopathy Severity Scale (ETDRS-DRSS), 33% of patients demonstrated a 2-step or greater improvement compared to 0% improvement in the observational control. Notably, 1 patient demonstrated a 4-step improvement in ETDRS-DRSS.¹⁴ Three of 7 NPDR patients (43%) and 2 of 8 PDR patients (25%) demonstrated a 2-step or greater improvement 3 months after study drug administration. One serious adverse event (SAE) was reported in cohort 1, occurring in the patient’s untreated fellow eye and was determined to be unrelated to the study drug.¹⁴ One patient experienced an adverse event (AE) of episcleritis, but resolved following topical corticosteroid therapy. Intraocular inflammation (IOI) was not observed and additional AEs in the study eye were mild and not drug related.¹⁴

Another phase 2 study, AAVIATE, is an active-controlled, dose-escalation trial that is evaluating the safety, efficacy, and tolerability of a single dose of NAV AAV8 vector encoding a transgene for anti-VEGF fab in wet AMD patients.¹⁵ Eyes were randomized into 1 of 3 treatment arms: a 3:1 ratio of single dose 2.5x10¹¹ GC/eye with monthly 0.5 mg ranibizumab IVT injection control; a 3:1 ratio of single dose 5x10¹¹ GC/eye with monthly 0.5 mg ranibizumab IVT injection control; and a 3:1 ratio of single dose 5x10¹¹ GC/eye with monthly 0.5 mg ranibizumab IVT injection control in NAb-positive patients.⁹ Extension study for AAVIATE will encompass cohorts 4 and 5; 15 patients will be dosed with 1x10¹² GC/eye and 20 NAb-positive patients will be dosed with 1x10¹² GC/eye, respectively.⁹

At 6 months, 14 patients demonstrated visual acuity stability with a mean best-corrected visual acuity (BCVA) change of -2.8 letters (95% CI: -7.0, 1.4) and central retinal thickness (CRT) stability with a mean change of -2.5 µm (-27.1, 22.0) measured from day 1.¹⁵ Five patients in the ranibizumab arm demonstrated a mean BCVA change of +6.8 letters (-3.3, 16.9) and stable CRT values with a mean change of -22.2 µm (-41.6, -2.8) at 6 months measured from day 1.⁹ Over 6 months, a 75.9% reduction in anti-VEGF treatment burden was demonstrated in cohort 1 patients as they received an average of 1.2 injections. Additionally, 4 patients received no treatments with a mean change of BCVA and CRT values remaining stable, +1.3 letters (-5.7, 8.2) and -5.8 µm (-49.5, 38.0), respectively.¹⁵ Study eye treatment-emergent AEs (TEAE) included mild conjunctival hemorrhage, and worsening wet AMD, with 4 cases of mild IOI.

One-time gene therapy in the SCS shows promise as a potential treatment option for patients with retinal diseases. The ongoing phase 2 studies AAVIATE and ALTITUDE will further elucidate the efficacy, durability, and safety of SCS-administered gene therapy for the treatment of wet AMD and DR. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by Bausch + Lomb.

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