From groundbreaking new therapies to ongoing clinical trials, is gene therapy set to transform the treatment landscape of retinal disorders?
When it comes to the management of retinal disorders, gene therapy is changing the game—promising to revolutionize retinal care. With advance in gene editing and targeted therapies, gene therapy offers more effective solutions for previously untreatable retinal conditions.
Over the last two decades, we have witnessed impactful advance in the management of many retinal disorders. What was once a field with limited options for restoring hope and preserving vision for patients with degenerative diseases now offers a growing and evolving array of treatments.
Among recent developments, gene therapy stands out for its potential to transform retinal disorder management—sparking optimism and enthusiasm among clinicians and patients alike.
Depending on the source or pathogenesis of the retinal disorder, gene therapy may take the form of gene editing, gene replacement, or non-gene-specific neuroprotective approaches to prevent cell death. It may also include introducing genes into cells to transform them into their own protein factories, such as anti-vascular endothelial growth factor (anti-VEGF) agents.
Currently, more than 50 pharmaceutical and biotech companies are actively pursuing gene therapy treatments in ophthalmology.
A new era in retinal disorder management
Dr. Amin Kherani, a vitreoretinal surgeon, associate clinical professor at the University of Calgary in Canada, and co-founder of Calgary Retina Consultants and Southern Alberta Eye Center, is optimistic about the potential of gene therapy.
“Gene therapy is an exciting development that could enable us to treat chronic retinal disorders, especially inherited and degenerative conditions such as macular degeneration and diabetes-related retinopathies and edema,” Dr. Kherani shared. “Given that these conditions cause significant visual disability and are progressive and currently incurable, gene therapy offers a promising source of hope.”
As we know, Spark Therapeutics’ Luxturna was the first to receive United States Food and Drug Administration (U.S. FDA) approval for the treatment of an inherited disorder, Leber congenital amaurosis type 2, in 2017. This landmark achievement was expected to pave the way for the next wave of ocular gene therapy candidates. Although some development programs are nearing completion, with pivotal trial data rolling in, Luxturna remains the sole approved therapy in this field.
Recent studies have explored gene augmentation for some of the more common retinal diseases and gene replacement for inherited retinal diseases. Dr. Geoff Williams, associate professor at the University of Calgary in Canada, co-founder of Calgary Retina Consultants, and medical director of Southern Alberta Eye Center (SAEC) Surgical, has certainly noted the surge in clinical development programs for gene therapy in retinal disease management.
Dr. Geoff Williams, associate professor at the University of Calgary in Canada, co-founder of Calgary Retina Consultants, and medical director of Southern Alberta Eye Center (SAEC) Surgical, has certainly noted the surge in clinical development programs for gene therapy in retinal disease management.
“There are currently about 40 clinical trials actively recruiting for ocular diseases, and over 160 trials completed or pending in this rapidly advancing area of ocular gene therapies,” Dr. Williams shared.
We have seen numerous methods and routes for delivering gene therapy, such as different vectors and various administration techniques, including intravitreal, subretinal, and suprachoroidal.
“Various strategies for gene manipulation are being used to alter disease characteristics, including cell-based vectors, adenovirus vectors, mRNA and other approaches,” he explained. “These varied approaches all carry with them a variety of advantages and potential complications that are still being explored.”
From trials to triumphs
So, which pipeline therapies are clinicians most excited about?
“I think the retina community is most interested in the gene therapies for retinitis pigmentosa, choroideremia, and X-linked retinoschisis, as these therapies could lead to the prevention of complete blindness,” shared Dr. Williams. “However, other therapies are closer to being in the hands of clinicians, such as the subretinal adenovirus vector for treatment of wet AMD, like RGX-314, which could reduce the need for ongoing injections in many patients.”
Gene therapy is often touted for its ‘one and done’ potential, especially for common retinal diseases that require regular and ongoing intravitreal injections.
RGX-314 (Regenxbio, Maryland, USA; AbbVie, Illinois, USA) is a frontrunner in AAV-based gene therapy, designed to deliver gene encoding for an anti-VEGF protein with the goal of sustained protein production within the retinal cells—potentially reducing or removing the need for frequent intravitreal injections.
In the Phase 1/2 trial involving 42 patients with neovascular AMD, subretinal RGX-314 demonstrated sustained vision gains at two years and a significant reduction in the need for anti-VEGF treatments. Pivotal phase 3 studies, ATMOSPHERE and ASCENT, with subretinal RGX-314 are currently underway. Additionally, RGX-314 via suprachoroidal delivery in the clinic is also being investigated in trials for the treatment of neovascular AMD and diabetic retinopathy.
As the number of patients who need treatment for AMD and diabetic eye disease continues to rise, the prospect of reducing both the patient and clinical burden is very attractive.
“Utilizing the biological factory to activate proteins (pharmaceuticals), which in turn may help slow the disease progression, could meaningfully reduce disability and burden—and hopefully offer a safe and effective pathway for improved outcomes,” explained Dr. Kherani.
Innovations in anti-VEGF gene therapy
Another entrant in the anti-VEGF protein-producing forum is ixoperogene soroparvovec (Adverum Biotechnologies, California, USA), an intravitreal AAV vector delivering an aflibercept coding sequence.
The phase 1 trial, OPTIC, demonstrated sustained protein levels, improved retinal thickness, and maintained visual acuity. Additionally, the majority of patients in the phase 2 trial did not require any anti-VEGF injections over a six-month period.
The PRISM trial of 4D-150 (4D Molecular Therapeutics) enrolled 51 neovascular AMD patients who required frequent anti-VEGF injections to manage their disease. Employing a different mechanism, 4D-150 has a dual anti-VEGF
transgenic approach, expressing both aflibercept and VEGF-C inhibitory RNA. Interim results have been positive, showing a reduction in annualized injection rates and improvement in visual acuity. In addition, 4D is also taking on choroideremia with 4D-110, which is currently conducting a phase 1/2 trial for patients with an identified CHM gene mutation.
Although two new agents for advanced dry AMD with geographic atrophy have recently been approved—treatments that previously did not exist—gene therapy is making significant strides in this space.
JNJ-1887, an intravitreal gene therapy candidate from Janssen (Beerse, Belgium), aims to increase the expression of a soluble recombinant version of CD59. This inhibits the formation of the membrane attack complex, the final step in complement-mediated cell lysis, thereby protecting retinal cells from further atrophy. Following promising phase 1 results, the program is now advancing to the phase 2 PARASOL trial.
Recent programs, such as JNJ-1887 and others, are showing that gene therapy delivery could be administered in-office and may not require a trip to the operating room. The intravitreal delivery route also caught the attention of clinicians.
“For me, the most surprising aspect of the JNJ trial is the single intraocular (not subretinal) injection for atrophic AMD, as this seems to be quite simple in implementation,” observed Dr. Williams.
For these treatments aimed at reducing or eliminating the injection burden by essentially having the eye produce its own anti-VEGF treatment, concerns have been raised about the inability to regulate its production or turn off the newly created anti-VEGF factory.
“I do worry about regulating the genes and being able to turn them on or off appropriately,” noted Dr. Kherani.
“While the issue of turning on and off a gene therapy remains an open question, I think for the most part, the localized applications directly to the eye—rather than systemic delivery—makes this concern less worrisome,” added Dr. Williams.
Impact and obstacles of gene therapy
Although the patient populations may be smaller, providing treatment and hope to those with inherited retinal disease is considered by many to be far more impactful.
Much of the recent research has focused on retinitis pigmentosa (RP), particularly on preserving or rescuing RPGR function. The phase 1/2 trial of sub-retinally delivered botaretigene sparoparvovec (MGT009) from MeiraGTx (New York, USA) and Janssen showed positive improvements in functional vision in RP patients. This progress has led to the ongoing phase 3 LUMEOS trial.
Beacon Therapeutics (Florida, USA) is planning their phase 2/3 study (VISTA) of subretinal laruparetigene zosaparvovec (AGTC-501) following observed improvements in retinal sensitivity on microperimetry in X-linked RP patients during their phase 1 study. Similarly, Biogen is looking to rescue the RPGR gene function. Although they did not meet retinal sensitivity endpoints in their early trial, they were motivated by improvement trends in low luminance visual acuity to proceed with the phase 3 trial, SOLSTACE.
New hope is also on the horizon for our X-linked retinoschisis patients, as Atsena Therapeutics (North Carolina, USA) moves forward with their subretinal gene therapy candidate, ATSN-201—delivering RS1 to patients with the identified mutation.
Preclinical and clinical data have been very promising, but challenges remain. These include ensuring effective transduction of target tissues, minimizing immunogenicity, and scaling manufacturing to the commercial level required to bring gene therapy a mainstream clinical option.
Furthermore, companies are evaluating strategies to combat challenges such as immunogenicity and other biological issues. However, scaling manufacturing to meet the anticipated demand for common anti-VEGF-treated diseases remains a big challenge. Additionally, considering the high cost of the currently available Luxturna—approximately $425,000 USD per eye—outside of clinical trials, the costs may become prohibitively high.
“I believe the biggest challenges will be the cost of these new therapies, as the development expenses are enormous,” confirmed Dr. Williams. “Even the currently available Luxturna is over $400,000, which is out of reach for many.”
“If these costs are going to be quite high, then access could be a real barrier, especially for those in public healthcare systems,” said Dr. Kherani. He added that access to these treatments may vary depending on how healthcare is structured in different countries.
Balancing breakthroughs and burdens
Indeed, it is an exciting time to witness the advancements in gene therapy for the management of both common and rare retinal disorders—offering treatment solutions where previously, in some cases, there were none.
Although gene therapy is set to make a significant impact on the growing number of patients requiring regular and frequent treatments for AMD and diabetic eye diseases, ensuring that these therapies reach all who could benefit may create its own burden on healthcare providers.
“I do believe that gene therapies will help reduce the burden on the system in the future,” Dr. Williams explained. “But in the short term, the system is too overloaded to accommodate complex and highly specific therapies for one person at a time.”
He cited the example of RGX-314 in the current pivotal studies, which require subretinal, surgical administration. “That’s why a single intravitreal injection or other in- office demonstration would be an enormous benefit compared to the complex surgical procedures or detailed genetic analysis required for less common diseases,” he explained.
With enthusiasm and optimism, we eagerly await the next therapeutic candidate to achieve regulatory approval and take its place within the current armamentarium of retinal disorder treatments. Only then, we can see if, and how, gene therapy transforms the management of patients with retinal disorders in real-world settings.
Editor’s Note: A version of this article was first published in PIE Magazine Issue 31.
