conference reporter

Potential of Gene Therapy for Age-Related Macular Degeneration

by Peter K. Kaiser, MD

Overview

Gene therapy has great potential in the treatment of a variety of relatively common retinal diseases. At AAO 2022, presentations on gene therapy included some studies in both wet and dry age-related macular degeneration (AMD).

Following the conference, featured expert Peter K. Kaiser, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Kaiser’s clinical perspectives on the emerging data are presented here.

Peter K. Kaiser, MD

Chaney Family Endowed Chair in Ophthalmology Research
Professor of Ophthalmology
Cleveland Clinic Lerner College of Medicine
Staff, Vitreoretinal Department
Cleveland Clinic Cole Eye Institute
Cleveland, OH

“Looking to the future, I think that there is tremendous excitement about gene therapy, especially for diseases such as diabetic retinopathy. Patients with diabetic retinopathy often present as young adults, and they need lifelong treatment with anti-VEGF therapy.”

Peter K. Kaiser, MD

Our focus here is on a type of gene therapy that uses a viral vector to transfect the ocular tissue to produce a protein of interest. In the case of dry AMD, there are several proteins of interest in the complement pathway (eg, CFI, CFH, and soluble CD59), and it is exciting that gene therapies incorporating these proteins are already underway.

One target is using gene therapy to produce recombinant CFI. At AAO 2022, Allen C. Ho, MD, provided an overview of the phase 1/2 FOCUS trial. FOCUS is evaluating the delivery of a CFI-targeted gene therapy (ie, GT005) for geographic atrophy seen in late dry AMD. He explained that the CFI transgene is delivered to the subretinal space via either a transvitreal approach or a suprachoroidal approach using a specially designed system (ie, Orbit SDS [Gyroscope Therapeutics Limited]). The Orbit SDS system accesses the subretinal space via a suprachoroidal approach in which a microneedle is advanced to the subretinal space through a flexible cannula, without the need for a vitrectomy or a retinotomy. 

The understanding of abnormal complement proteins and their role in AMD is not always clear, so work continues to further elucidate mutations and their associations with AMD phenotypes. For example, a poster presented by Cláudia Farinha, MD, at the meeting showed that carriers of rare CFH variants have more severe disease and are likely at an increased risk of progression relative to noncarriers. This group also reported that carriers had a greater drusen burden in the macula, more pigment epithelial detachments, and thinner retinas compared with noncarriers.

The CD59 protein is a naturally occurring inhibitor of the assembly of the complement membrane attack complex. JNJ-81201887 is a gene therapy that produces the soluble CD59 protein, halting this terminal step in the complement cascade in an attempt to halt the progression of geographic atrophy secondary to AMD. Michael Nathan Cohen, MD, presented safety and tolerability data from a phase 1 trial of this investigational gene therapy. With 2 years of follow-up, there were no serious adverse events or systemic serious adverse events noted, although inflammation was a key adverse event, with 29% of patients developing mild inflammation that resolved with either topical steroids or observation alone. 

We have much more data from trials of gene therapy for wet AMD, where the importance of the VEGF protein has long been recognized. At AAO 2022, Peter A. Campochiaro, MD, reviewed ongoing gene therapy programs for wet AMD, including RGX-314, an AAV8 vector expressing an anti–VEGF-A Fab that is similar to ranibizumab. RGX-314 showed maintained or improved best-corrected visual acuity out to 2 years in a phase 1/2a study and is now undergoing further evaluation in 2 studies. 

Whether considering wet or dry AMD, there are essentially 3 different approaches to the delivery of gene therapy: the intravitreal injection, subretinal surgery, and the suprachoroidal approach. The original method (ie, the intravitreal injection) is, by far, the simplest approach, but it has some drawbacks. For instance, the injected gene therapy must cross through the vitreous to transfect the retinal cells, which requires the use of a higher dose. Further, the intravitreal injection, itself, may be associated with intraocular inflammation. And, for patients who have had prior exposure to a virus resembling the viral vector, their immune systems may recognize the vector. As a result, there is the potential for additional inflammation and lower rates of transfection.

Subretinal surgery is another approach to the administration of gene therapy. This may be the most technically difficult method, and it cannot be performed in the office. However, it has very low inflammatory potential, and, in the setting of neutralizing antibodies from the patient, this route may be preferred in the sense that the subretinal space is more immune privileged than the vitreous.

The suprachoroidal approach is very new at this stage. Thus far, it may offer the best of both worlds in that it appears to cause less inflammation than the intravitreal injection, it does not require a higher dose, and it may not be overly challenging to perform. It is early days for the suprachoroidal approach, however, and the intravitreal and subretinal routes have more data. So, we have 3 different approaches, but I do not believe that we have any clear answers yet as to which method may be optimal.

Looking to the future, I think that there is tremendous excitement about gene therapy, especially for diseases such as diabetic retinopathy. Patients with diabetic retinopathy often present as young adults, and they need lifelong treatment with anti-VEGF therapy. It would be a major breakthrough if gene therapy could be administered once, leading to the production of anti-VEGF treatment indefinitely by the retinal cells.

References

Campochiaro PA. Gene therapy for neovascular AMG. Section XV: gene- and cell-based therapies. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

ClinicalTrials.gov. Pivotal 1 study of RGX-314 gene therapy in participants with nAMD (ATMOSPHERE). Updated May 6, 2022. Accessed October 12, 2022. https://clinicaltrials.gov/ct2/show/NCT04704921

ClinicalTrials.gov. Pivotal 2 study of RGX-314 gene therapy in participants with nAMD (ASCENT). Updated June 7, 2022. Accessed October 12, 2022. https://clinicaltrials.gov/ct2/show/NCT05407636

Cohen MN. Phase 1 study of JNJ-81201887 gene therapy in geographic atrophy (GA) due to age-related macular degeneration (AMD). Section X: late-breaking developments, part II. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

de Guimaraes TAC, Georgiou M, Bainbridge JWB, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol. 2021;105(2):151-157. doi:10.1136/bjophthalmol-2020-316195

Dreismann AK, McClements ME, Barnard AR, et al. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021;28(5):265-276. doi:10.1038/s41434-021-00239-9

Farinha C, Barreto P, Coimbra R, et al. Phenotypic expression of CFH rare variants in age-related macular degeneration patients in the Coimbra Eye Study. Invest Ophthalmol Vis Sci. 2022;63(9):5. doi:10.1167/iovs.63.9.5

Farinha C, Barreto P, Coimbra R, et al. Phenotypic expression of CFH rare variants in AMD patients: the Coimbra Eye Study. Poster presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL. Poster PO404.

Geerlings MJ, de Jong EK, den Hollander AI. The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment. Mol Immunol. 2017;84:65-76. doi:10.1016/j.molimm.2016.11.016

Ho AC. Gene therapy for atrophic AMD 2022. Section XV: gene- and cell-based therapies. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

Khanani AM, Thomas MJ, Aziz AA, et al. Review of gene therapies for age-related macular degeneration. Eye (Lond). 2022;36(2):303-311. doi:10.1038/s41433-021-01842-1

Kumar-Singh R. The role of complement membrane attack complex in dry and wet AMD—from hypothesis to clinical trials. Exp Eye Res. 2019;184:266-277. doi:10.1016/j.exer.2019.05.006


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