Gene therapy in ocular disease spurs excitement with some caution
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It has been decades since the concept of gene therapy emerged in the ophthalmology field.
Excitement was renewed with the 2017 approval of Luxturna (voretigene neparvovec, Spark Therapeutics) for patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.
Source: Kyle Alexander
Gene therapy has also shown significant potential in ongoing clinical trials for age-related macular degeneration, geographic atrophy and diabetic retinopathy.
“The approval of Luxturna launched the ophthalmology field into looking at other indications for gene therapy to be approved. This has opened the field for a biofactory approach, where we are using gene therapy to produce a protein in the eye to either stop retinal disease or slow it down,” OSN Retina/Vitreous Board Member Arshad M. Khanani, MD, MA, said. “Gene therapy is a paradigm shift in the treatment of retinal diseases, and there are multiple programs in various stages of development. However, there is still work to be done, including the assessment of long-term efficacy and safety and identifying the best prophylaxis for our patients so that we can truly utilize gene therapy to help maintain our patients’ long-term vision.”
Early results
In addition to inherited retinal diseases, a one-time gene therapy treatment is being explored for AMD as well as diabetic retinopathy.
“We are looking at gene therapy for neovascular age-related macular degeneration (nAMD) as anti-VEGF injections have revolutionized the treatment for nAMD, but outcomes in the real-world setting are not optimal because patients are not receiving enough injections compared to what they do in clinical trials,” Khanani said. “Having a biofactory approach to produce anti-VEGF with one-time gene therapy treatment to control disease activity by eliminating the need for anti-VEGF injections or significantly decreasing treatment burden would benefit a large number of patients in maintaining better long-term vision.”
Rachel M. Huckfeldt, MD, PhD, a retina specialist at Massachusetts Eye and Ear, said that a one-time gene therapy injection to replace the treatment burden of numerous monthly trips to a retina specialist’s office would benefit many patients.
“We have more tools coming,” Huckfeldt said. “Data presented by Editas in fall 2021 showed safety and signs of efficacy for what was at the time first-in-human CRISPR-Cas9 genome editing for a form of Leber congenital amaurosis due to problems in the CEP290 gene. This technique of genome editing is barely a decade old, and we are already bringing it to patients as a potential tool to treat retinal diseases.”
Promising interim results have been reported for gene replacement therapy in other forms of inherited retinal disorders.
“We have seen promising interim results reported from companies that are testing gene replacement therapies for other forms of inherited retinal disorders,” Huckfeldt said. “For example, efforts have been made to develop gene augmentation therapy for X-linked retinitis pigmentosa due to the RPGR gene. There have been promising results on both safety and efficacy from phase 1/2 trials that are now leading to later-stage trials.”
Results of the MGT009 phase 1/2 trial showed the investigational gene therapy botaretigene sparoparvovec (MeiraGTx/Janssen) appeared safe and improved vision in patients with X-linked retinitis pigmentosa with disease-causing variants in the RPGR gene. The novel therapy is now under evaluation in the phase 3 Lumeos study.
AGTC also conducted a phase 1/2 trial for X-linked retinitis pigmentosa, with results supporting advancement of AGTC-501 to the phase 2/3 VISTA trial, according to Huckfeldt.
Gene therapy has shown potential in diabetic retinopathy.
The multicenter, open-label, randomized, controlled, dose-escalation phase 2 ALTITUDE trial is evaluating in-office suprachoroidal RGX-314 (Regenxbio) as a one-time treatment for diabetic retinopathy. RGX-314 uses AAV8 to deliver a gene that encodes a monoclonal antibody fragment designed to neutralize vascular endothelial growth factor. In cohort 1 of the trial, 15 participants received treatment with 2.5 × 1011 GC per eye, and five participants were kept under observation as controls. In cohorts 2 and 3, a higher dose level of RGX-314 is being evaluated.
“The ALTITUDE study recently completed enrollment, and more data will be presented in the future. The data from cohort 1 has shown that the treatment has been well tolerated so far with an impressive efficacy signal in terms of diabetic retinopathy regression after a single injection of RGX-314 in the suprachoroidal space,” Khanani said. “It is still early data, but it is promising to see that at 6 months, we are seeing a two-step or greater regression in 57% of the patients with baseline [Diabetic Retinopathy Severity Scale] 47/53, which is similar to 55% seen in the PANORAMA study with every 8 weeks aflibercept. I am looking forward to the long-term efficacy and safety data from the ALTITUDE study.”
Other anticipated results
Experts are eagerly awaiting the results of various other ongoing trials.
“There are many gene therapy trials that will have readout within the next couple of years. Some are still in the early phase and others are in pivotal phases, but it will be interesting to see how these all play out,” Daniel C. Chung, DO, MA, chief medical officer of SparingVision, said. “In recent years, we have seen the development of other therapeutic strategies, including antisense oligonucleotide, which is a little different because it acts on the RNA portion of the process of making the protein. We also have gene editing coming into play now, as well as some gene independent approaches for rod-cone dystrophies. There are a number of tools in the tool kit aiming to address some of the genetic retinal diseases, which appear very promising, and we hopefully will have more shots on goal to give our patients more options because this is obviously an area of high unmet need.”
Khanani agreed.
“We hope to have data from the ongoing pivotal surgical subretinal gene therapy trials of RGX-314 (ATMOSPHERE and ASCENT) within the next few years and hopefully have the first gene therapy for nAMD available by 2025, if the trials meet the primary endpoints,” Khanani said. “We have also seen promising long-term efficacy and disease control in patients with nAMD treated with intravitreal gene therapy with ADVM-022 in the OPTIC trial. Intraocular inflammation with ADVM-022 has been noticed in the OPTIC trial, and long-term inflammation was mainly seen in patients treated with the high dose. Dose ranging is critical for gene therapy, and finding the lowest dose with good efficacy and manageable safety is important. The LUNA phase 2 trial with ADVM-022 is looking at the lower doses with more extensive prophylaxis to minimize long-term inflammation. Suprachoroidal gene therapy is also another exciting in-clinic approach for nAMD patients, and this is being looked at in the AAVIATE phase 2 trial with RGX-314. As a field, we need to continue to work on the best routes of delivery for gene therapy, the best vector and the best prophylaxis to use. Nevertheless, I am thrilled and excited because being involved in many of the gene therapy trials, I have seen efficacy that can help our patients decrease their treatment burden and hopefully maintain long-term vision.”
“We are eager to see how these ongoing trials pan out,” Andreas K. Lauer, MD, chair of the department of ophthalmology and Thiele-Petti Endowed Chair at OHSU Casey Eye Institute, said.
“Gene therapy has been revolutionary in the ophthalmology field. This is truly an important moment in humankind that we are able to deliver gene therapy in a living human and have that person express a protein that’s important for vision that they have never been able to do in their life and, as a result, preserve their vision,” Lauer said. “In the case of Leber congenital amaurosis, Luxturna improved the vision for many patients, which was never possible until that treatment became approved. We are excited to be able to treat other conditions as well in the other trials that are underway.”
Challenges
Despite the excitement regarding the research that is underway, challenges remain.
“One challenge is the body’s response to receiving gene therapy. For years now, we have been aware of gene therapy-induced inflammation or the body’s response in which inflammation develops a few weeks after receiving gene therapy,” Lauer said. “The good news is that we know how to deal with it now. We use immunosuppressive medication at the time of surgery and shortly after to minimize the effect, and we have a relatively good handle on that.”
However, more research is needed about the body’s immune response to gene therapy, which is especially important when the second eye is treated, Lauer said.
“At present, we treat the first eye, and then the other eye is treated 1 week later. The reason for doing this is to get the immunosuppressive medication in before the immune system responds adversely,” he said. “But we need to better understand how to prevent the immune system from overreacting to the viral vector because inflammation in the eye can be harmful. This is one area that we are really learning about now and has been a new area of understanding.”
Chung agreed that there are challenges to overcome regarding inflammation as well as issues with safety.
“This is all a mixed bag because there is a lot of excitement with gene therapy, but we have had some challenges with safety signals associated with gene therapy, mainly inflammation,” Chung said. “There are also some new safety signals from some patients receiving Luxturna on clinical trial with atrophy after injection in parts of the retina.”
Huckfeldt said that in tandem with the encouraging signals observed in early-phase trials, “We have been reminded in more ways than one that the gene therapy field is still new.”
“Within the past year, we’ve seen late-phase clinical trials for inherited retinal disorders not meet their primary outcome. One was the phase 3 STAR study for choroideremia. Last summer, that trial did not successfully meet its primary endpoint of a three-line gain in visual acuity, and [Biogen] also reported that the trial did not meet key secondary endpoints,” Huckfeldt said. “Then, earlier this year, results of the phase 2/3 Illuminate trial of antisense oligonucleotides [from ProQR] to treat a form of Leber congenital amaurosis were released, and here too, the trial did not meet its primary endpoint. On the one hand, these results are disappointing, but we can also see them as an opportunity to ask important questions about why the endpoints weren’t achieved and what we need to do differently moving forward.”
Identifying the safest way to deliver gene therapy is yet another challenge.
“How we can perform this surgical procedure of placing gene therapy in the subretinal space and do so in the least harmful and the most effective way is what I think about all the time,” Lauer said. “Refining surgical technique has been an area of interest of mine and many others, and there have been some techniques that have shown improvement. We can further improve surgical technique with better instrumentation that controls the injection speed as well as devices that could help hold everything still and dampen any surgeon’s movement that is not necessary. So, there have been technologic developments in that regard.”
Researchers also need to identify the best route to administer gene therapy.
“For ocular gene therapy, there are three primary routes, the most common of which is injecting the medication in the subretinal space through a procedure called vitrectomy,” Lauer said. “Another is to inject the medication into the vitreous, and we’re finding that that’s not proven to be a good way to go with the current viral vector technology because the immune system seems to react negatively to it, and many of those studies have seized early on.”
Lauer said there is ongoing research assessing gene therapy administration into the suprachoroidal space.
“There is a small potential space between the sclera and the choroid for which there is a technique to be able to administer medication there,” he said. “The advantage is that it doesn’t require vitrectomy and is therefore less invasive. We are trying to understand whether that is a good way to go and if it will be less recognized by the immune system. We’re still working to refine and define the best method for administering gene therapy for our patients. At present time, the subretinal surgery approach is most commonly performed because placing the medication there appears to be the best way to keep the immune system from reacting.”
Study endpoints remain a significant issue in clinical development of gene therapy.
“There have been positive anecdotal impressions from participants of clinical trials, but unfortunately, the trials did not meet clinical meaningfulness on a cohort level,” Chung said. “We must really look at whether the endpoints are truly appropriate for these rare diseases, and we must examine clinical trial designs and patient numbers. Those are some of the challenges that we must overcome and really learn more about.”
The future
Despite these challenges, the future of gene therapy in ophthalmology is promising.
“There are definitely more questions to be answered, but the reality is that the gene therapy that is commercially available is impacting lives in a very positive way. It has given patients an option,” Chung said. “The field is very promising, and we are doing a lot to meet this burden of unmet need for these patients.”
Huckfeldt said the field will continue to become more sophisticated as researchers gain experience in gene therapy and learn how the stage of retinal disease intersects with the treatment potential.
“We know that we need a cellular target for gene therapy, but are there stages of disease that are more or less amendable to a meaningful treatment response with gene therapy? We also need to develop a better understanding of the complications that are hopefully infrequent, such as with the reports regarding a subset of patients treated with Luxturna post-FDA approval,” Huckfeldt said. “The field is also focusing on understanding inflammation that can accompany genetic therapies so that we have better ways of treating it.”
Lauer said that this is a new era in ophthalmology.
“Gene therapy is a blessing and holds a lot of promise for patients and their families, especially for inherited retinal conditions,” he said. “Being able to provide hope for families is tremendous. For many years, these patients have been told that there is nothing that we can do, so being able to offer gene therapy as a potential treatment is tremendous and incredibly meaningful. However, these are still the early days, and we need to continue to understand how best to deliver gene therapy in the safest possible way. There is still a lot of work to be done, but it is all very exciting and is only going to get better.”
- References:
- Biogen announces topline results from phase 3 gene therapy study in choroideremia. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-topline-results-phase-3-gene-therapy-study. Published June 14, 2021. Accessed July 21, 2022.
- Dhurandhar D, et al. Indian J Ophthalmol. 2021;doi:10.4103/ijo.IJO_3117_20.
- Ip MS. Update on gene therapy for diabetic retinopathy. Presented at: Retina 2022; Jan. 15-21, 2022; Waikoloa, Hawaii.
- Khanani AM, et al. Eye (Lond). 2022;doi:10.1038/s41433-021-01842-1.
- Regenxbio announces initiation of second pivotal trial in RGX-314 clinical program for the treatment of wet AMD using subretinal delivery (press release). https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-initiation-second-pivotal-trial-rgx-314. Published Jan. 10, 2022. Accessed July 18, 2022.
- Regenxbio presents positive interim data from phase 2 ALTITUDE trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-presents-positive-interim-data-phase-ii-altitudetm. Published Feb. 12, 2022. Accessed July 18, 2022.
- X-linked retinitis pigmentosa. https://agtc.com/programs/x-linked-retinitis-pigmentosa/. Accessed Aug. 1, 2022.
- For more information:
- Daniel C. Chung, DO, MA, can be reached at SparingVision, Three Logan Square, 1717 Arch St., Philadelphia, PA 19103; email: daniel.chung@sparingvision.com.
- Rachel M. Huckfeldt, MD, PhD, can be reached at Massachusetts Eye and Ear, 243 Charles St., Boston, MA 02114; email: rachel_huckfeldt@meei.harvard.edu.
- Arshad M. Khanani, MD, MA, can be reached at Sierra Eye Associates, 950 Ryland St., Reno, NV 89502; email: arshad.khanani@gmail.com.
- Andreas K. Lauer, MD, can be reached at OHSU Casey Eye Institute Retina Clinic, Marquam Hill, 545 S.W. Campus Drive, Portland, OR 97239; email: lauera@ohsu.edu.
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