In recent years, significant advances in treatment options for neovascular (exudative, or “wet”) age-related macular degeneration (AMD) have dramatically improved outcomes for these patients. However, there is still no FDA-approved therapy for nonexudative (or “dry”) AMD, which represents up to 90% of all AMD cases.¹ If dry AMD progresses to geographic atrophy (GA), it results in devastating, irreversible visual consequences. This coupling of poor outcomes and lack of current therapies for dry AMD means there is a large, unmet need for continued research, particularly around gene therapy.

Just over 5 years ago, the FDA approved voretigene neparvovec (Luxturna; Spark Therapeutics) for RPE65-mediated inherited retinal dystrophy (IRD).^2,3 Since then, gene therapy has shown promise as a prospective treatment for both inherited and acquired retinal diseases. There has been a surge of clinical trials investigating the potential role of gene therapy to treat both wet and dry AMD. As with all new frontiers, there has been both failure and growth. First-generation trials did not demonstrate the desired efficacy in the treatment of wet AMD. However, improved vectors and mechanisms of delivery have propelled this technology forward, with several in-human clinical trials focused on dry AMD and GA.

UNDERSTANDING GENE THERAPY

Gene therapy is the use of genetic material to treat disease. Classically, as in the Luxturna example noted previously, this involves replacing a defective gene like RPE65 with a normal copy that will then replenish a deficient or nonfunctioning protein to reverse the phenotype. This approach is the mainstay for treatment of IRD. In noninherited diseases like AMD, the idea is to create an ocular “biofactory” by inserting a gene that will produce a desired protein or cell that is either already available (leading to overproduction) or not normally produced in the eye (eg, a VEGF inhibitor).

Viral vectors are often used to deliver therapeutic gene products into the eye. When choosing a vector, safety, cloning capacity, and tissue tropism are important considerations. Adeno-associated viral (AAV) vectors are the most common type used to treat ophthalmic disease, although there are others, and based on the serotype can transduce different cell types.⁴ The optimal delivery method may vary depending on the vector used. For example, the capsid of AAV2 binds heparin-sulfate proteoglycan.⁵ This is copious in the subretinal space and less prevalent in the suprachoroidal space, making subretinal delivery of this vector most efficacious. The internal limiting membrane of the retina is rich in heparin sulfate, making intravitreal delivery less effective because AAV2 binds to this barrier.⁵ The binding capabilities of a given vector can be changed and exploited with the alteration of the capsid.

As previously mentioned, the delivery method of the vector is important for safety and efficacy. The current methods available are intravitreal, subretinal, and suprachoroidal. The standard technique for accessing the subretinal space involves a pars plana vitrectomy, retinotomy, and delivery of the therapeutic agent. A technique currently in phase 2 clinical trials uses the proprietary Orbit Subretinal Delivery System (Gyroscope Therapeutics), which allows therapeutic delivery to the subretinal space without vitrectomy via cannulation of the suprachoroidal space and deployment of a microneedle into the subretinal space when in the desired location.^6,7

Age-related macular degeneration is a multifactorial disease, with both genetic and environmental elements contributing to disease development and progression. Recent studies have shown the complement system to impact the pathogenesis of drusen formation and GA as well as significant associations between AMD development and variants of complement-associated genes (eg, complement factors H and B).^8-10 The 3 arms of the complement system are distinct but converge with the cleavage of C3 and C5 and subsequent formation of the membrane attack complex (MAC) that leads to cell death.¹⁰ Current gene therapy trials aim to inhibit the complement cascade through varying mechanisms to slow or halt progression of GA in dry AMD.

CURRENT TRIALS

In 2017, Hemera Biosciences conducted the first clinical trial for a gene therapy product to treat dry AMD. A phase 1, open-label, multicenter, dose-escalating, safety and tolerability study investigated intravitreal delivery of AAVCAGsCD59, which increases retinal cellular expression of a soluble, recombinant CD59 molecule.¹¹ CD59 occurs naturally in the body and inhibits the MAC, preventing complement-mediated cell lysis. The phase 1 trial evaluated 3 different dose cohorts injected in 17 eyes with GA; it lasted 26 weeks, with an additional 18 months of safety evaluation. Results presented by Janssen, which acquired the rights to AAVCAGsCD59 (now named JNJ-81201887), showed all 3 doses met the primary endpoint of safety. Results also showed a continual decline in lesion growth over 6-month increments in all 3 doses. JNJ-1887 has been granted Fast Track designation by the US Food and Drug Administration (FDA). Per their website, Janssen is planning a phase 2 trial to evaluate change in geographic lesion growth in patients treated with JNJ-1887 vs sham.¹²

The only other gene therapy currently in clinical trials is GT005 (Gyroscope Therapeutics). GT005 uses an AAV vector that promotes increased expression of complement factor I (CFI) protein. CFI inhibits complement-mediated cellular apoptosis. In contrast to the intravitreal delivery of AAVCAGsCD59, GT005 is delivered via subretinal injection using Gyroscope’s Orbit delivery system as well as through a traditional subretinal bleb technique.

There are several trials evaluating GT005 in the treatment of GA. FOCUS, a phase 1/2 multicenter study, was the first of these trials and evaluated dose escalation and safety of a single subretinal injection of GT005 with 48 weeks of follow-up in a cohort of 56 patients.¹³ Interim data demonstrated good tolerability with sustained increased levels of CFI in the vitreous and reduction in downstream biomarkers. This study is currently listed as active, not recruiting.

There are currently 2 phase 2 trials recruiting for GT005 in dry AMD patients. EXPLORE is a multicenter, randomized safety and efficacy study of low-dose vs high-dose GT005 vs sham in a 1:1:1 ratio in 75 patients with a rare genetic variant of the CFI gene associated with low levels of CFI.⁶ The primary outcome will seek to measure progression of GA after injection over a 48-week period. HORIZON is a parallel multicenter, randomized safety and efficacy study of medium-dose and high-dose GT005 vs sham in a 1:1:1 ratio.⁷ This phase 2 trial seeks to evaluate whether increased CFI expression leads to a clinically significant decrease in progression of geographic atrophy in a larger cohort of 250 patients, including those with rare CFI variants and those with foveal-sparing GA, over a 96-week study period.

FUTURE DIRECTIONS

The mechanisms underlying the pathogenesis of AMD are still not completely understood, making efficacious, targeted, and durable therapy a continuing challenge. Current gene therapy trials are evaluating intervention via different components in the complement system. Recently, it has been shown that a target outside the complement cascade may provide a new pathway for gene therapy in the treatment of dry AMD. A letter recently published in Clinical and Translational Medication demonstrated the benefit of gene therapy that directly targets mitochondrial dysfunction in murine and cellular models of dry AMD.¹⁴ Continued research is necessary and will further elucidate possible disease targets.

Gene therapy has come a long way since the first FDA-approved treatment for ocular disease in 2017. There is potential for great impact as we move toward a world where precision medicine is commonplace. Further development of optimal vectors and delivery techniques are necessary to advance the technology and increase its potential impact. Efficacy and safety outcomes from current trials will aid in further refinement. RP

REFERENCES

1. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102(11):1640-1642. doi:10.1001/archopht.1984.01040031330019
2. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomized, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860. doi:10.1016/S0140-6736(17)31868-8
3. Spark Therapeutics. FDA approves Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), a 1-time gene therapy for patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. News release. December 19, 2017. Accessed February 6, 2023. Accessed December 2022. https://sparktx.com/press_releases/fda-approves-spark-therapeutics-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-for-patients-with-confirmed-biallelic-rpe65-mutation-associated-retinal-dystrophy/
4. Ramlogan-Steel CA, Murali A, Andrzejewski S, Dhungel B, Steel JC, Layton CJ. Gene therapy and the adeno-associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: trials, future directions, and safety considerations. Clin Exp Ophthalmol. 2019;47(4):521-536. doi:10.1111/ceo.13416
5. Boye SL, Bennett A, Scalabrino ML, et al. Impact of heparan sulfate binding on transduction of retina by recombinant adeno-associated virus vectors. J Virol. 2016;90(8):4215-4231. doi:10.1128/JVI.00200-16
6. EXPLORE: a phase II study to evaluate the safety and efficacy of 2 doses of GT005 (EXPLORE). ClinicalTrials.gov Identifier: NCT04437368. Updated December 5, 2022. Accessed February 6, 2022.
7. HORIZON: a phase II study to evaluate the safety and efficacy of 2 doses of GT005. ClinicalTrials.gov Identifier: NCT04566445. Updated December 16, 2022. Accessed February 6, 2022.
8. Khandhadia S, Cipriani V, Yates JR, Lotery AJ. Age-related macular degeneration and the complement system. Immunobiology. 2012;217(2):1271146. doi:10.1016/j.imbio.2011.07.019
9. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835. doi:10.1097/IAE.0000000000001392
10. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29(2):95-112. doi:10.1016/j.preteyeres.2009.11.003
11. Treatment of advanced dry age-related macular degeneration with AAVCAGsCD59. ClinicalTrials.gov Identifier: NCT03144999. Updated April 2, 2021. Accessed February 6, 2023.
12. Cohen MN, et al. Phase 1 study of JNJ-81201887 gene therapy in geographic atrophy (GA) due to age-related macular degeneration (AMD). Abstract #30071749. Presented at the 2022 American Academy of Ophthalmology Annual Meeting.
13. FOCUS: first in human study to evaluate the safety and efficacy of GT005 administered in subjects with dry AMD. ClinicalTrials.gov Identifier: NCT03846193. Updated December 1, 2021. Accessed February 6, 2023.
14. Millington-Ward S, Chadderton N, Finnegan LK, et al. AAV-mediated gene therapy improving mitochondrial function provides benefit in age-related macular degeneration models. Clin Transl Med. 2022;12(8):e952. doi:10.1002/ctm2.952.