UPMC Vision Institute Begins Clinical Use of Luxturna® Gene Therapy for Inherited Retinal Dystrophies
August 19, 2024
In July 2024, the UPMC Vision Institute treated its first patient with the gene therapy Luxturna® for inherited retinal dystrophies (IRD) caused by biallelic mutations in the RPE65 gene.
Luxturna® was the first gene therapy for any disease approved by the U.S. Food and Drug Administration (FDA) in late 2017.
“While IRDs in general are rare diseases and the biallelic RPE65 mutation variants even more so, Luxturna’s demonstrated efficacy provides our patient population the ability to halt the progression of their disease and hopefully maintain their remaining functional vision capacity,” says Joseph Martel, MD, assistant professor of Ophthalmology in the Department of Ophthalmology at the University of Pittsburgh School of Medicine.
About Luxturna for IRD
Luxturna is the first gene therapy approved by the FDA for treating IRDs. Errors in various genes important in maintaining retinal integrity may result in accelerated retinal degeneration with progressive vision loss, eventually resulting in blindness. Luxturna is designed to slow or halt this degeneration by delivering a functional copy of the RPE65 gene into the subretinal space, the area between the photoreceptors and the retinal pigment epithelium (RPE).
The therapy represents a significant advancement for those affected by RPE65-related IRDs, offering hope of preserving vision and improving quality of life for eligible patients.
"By restoring the function of the RPE65 gene, Luxturna can help preserve the remaining photoreceptors, which are crucial for maintaining vision," says Dr. Martel. “However, it is important to note that while Luxturna can prevent further degeneration, it is not capable of restoring vision that has already been lost due to irreversible damage to the photoreceptors. Once the cells are gone, they're gone forever – at least right now with our current tools and therapies. The therapy's main role is preservation, not restoration.”
Eligibility for Luxturna is limited to patients with confirmed biallelic mutations in the RPE65 gene who still have enough viable retinal cells to benefit from the therapy.
"This therapy is most effective in younger patients who are earlier in the disease process, where there is still a substantial amount of retinal function to preserve," says Dr. Martel. “But patients of any age over 12 months can receive the therapy if they are good candidates.”
The Importance of Increased Awareness for the Therapy
Because of the relative newness of the therapy, Dr. Martel explains the importance of reaching out to patients who may have been diagnosed with IRDs in the past but were never genetically tested or have been lost to follow-up over time because there simply were no treatment options or therapies available to them.
"There are likely patients who have been told in the past that there was nothing that could be done for their condition, and they may have stopped seeking care. These are the patients who could potentially benefit from Luxturna or other emerging therapies,” says Dr. Martel. “It’s crucial that we get the word out to as many people as possible because, though very rare, there are undoubtedly individuals out there that could benefit.”
The rapidly evolving field of gene therapy for retinal diseases makes it more important than ever to identify these patients who might now have treatment options that were previously unavailable. Increasing awareness and encouraging genetic screening among this population could lead to more patients being able to preserve what remains of their vision and improve their quality of life.
Becoming a Certified Luxturna Therapy Center
The process of becoming a certified center to administer Luxturna at the UPMC Vision Institute was rigorous. To administer Luxturna, centers must meet several stringent criteria, including expertise in inherited retinal diseases and experience with gene therapy. They must have the necessary surgical capabilities for the precise subretinal injection procedure and offer comprehensive post-treatment care and monitoring. Compliance with regulatory standards, robust patient support services, and collaboration with Spark Therapeutics are also mandatory elements of the program. Collectively this ensures that only qualified centers with the appropriate infrastructure and expertise are conducting the procedures.
As Dr. Martel explains, UPMC became an operational Luxturna therapy center in 2021, even though the first patient was only recently treated due to the rarity of the disorder. The certification process included an onsite visit from Spark Therapeutics to assess whether UPMC had the necessary infrastructure and expertise to safely and effectively administer the therapy.
A key aspect of this certification involved evaluating the pharmacy facilities, as the preparation and storage of Luxturna are highly specialized.
“The gene therapy product has a very narrow window for preparation and administration, typically within four hours,” says Dr. Martel.
Additionally, both the UPMC Vision Institute surgical team and UPMC pharmacy staff had to undergo specific training for administering the therapy. Dr. Martel attended a certification course in 2021 to master the precise subretinal injection technique required for administering Luxturna.
"The certification process ensures that we have the necessary pharmacy infrastructure, surgical expertise, and operating room capabilities to safely and effectively deliver the therapy," says Dr. Martel.
Administering the Treatment
Administering Luxturna requires a highly specialized procedure, orchestrated by a team with specific training and expertise.
“It’s a complex process that involves pharmacy training, special storage conditions, and coordination with the surgical teams,” says Dr. Martel. “The pharmacy team at UPMC Mercy, plays a critical role in this process.”
The surgical procedure begins with a vitrectomy that clears the vitreous gel from the eye to allow better access to the retina and more optimal instrument control by the surgeon.
"After the vitrectomy, we then use a very small, 38 gauge needle to administer the gene therapy product into the sub-neurosensory retinal space, which lies between the RPE and the photoreceptors,” says Dr. Martel.
The therapeutic, which is a liquid in lipid form and in a 300 microliter dose, once injected hydro-dissects the neurosensory portion of the retina from the RPE facilitating entry of the gene therapy into the target space.
This subretinal injection must be precise and is aided by advanced imaging technologies, including microscope-integrated optical coherence tomography (OCT), to ensure accurate placement. Dr. Martel also explains that they have begun using a microinjector system coupled with the OCT imaging platform, which the surgeon is able to manipulate with a foot pedal, to allow for a high level of precision and a slow infusion rate that reduces the risk of injury.
“The system also affords us the ability to more precisely titrate the volume we want to inject into the subretinal space,” says Dr. Martel.
Dr. Martel also emphasizes that Luxturna is intended as a "one-and-done" treatment. Both eyes are typically treated, but not simultaneously. The second eye is usually treated a few weeks after the first to ensure patient stability and monitor the patient for any complications.
"While each eye is treated separately, the treatment is designed to be administered only once per eye," Dr. Martel says.
About the Multidisciplinary Retinal Dystrophy Clinic at UPMC
The UPMC Vision Institute’s Retinal Dystrophy Clinic is a multidisciplinary center designed to provide comprehensive care for patients with inherited retinal dystrophies. The clinic features a team of specialists, including retinal surgeons, low vision optometrists, and genetic counselors.
"Our genetic counselors play a crucial role in coordinating patient care, from genetic testing to insurance approvals, ensuring that each patient’s treatment journey is as smooth as possible," says Dr. Martel.
This integrated approach allows for personalized treatment plans that address the unique needs of each patient, from diagnosis through post-treatment care.
Other Gene Therapy Clinical Trials in Progress at UPMC
In addition to offering Luxturna clinically, the UPMC Vision Institute is actively involved in several gene therapy trials aimed at treating a variety of retinal diseases. One of the key trials underway is the PRODYGY trial, sponsored by Sparing Vision. This trial is investigating the efficacy of a subretinal administered gene therapy that is not gene-specific, making it what is known as a "gene-agnostic" therapy.
"This means that the therapy could potentially benefit patients with retinal degeneration, regardless of the specific genetic mutation responsible for their condition," says Dr. Martel.
The PRODYGY trial centers on the production of a neurotrophic factor called rod-derived cone viability factor (RdCVF). This factor plays a critical role in preserving cone photoreceptors. RdCVF enhances the integrity and metabolic activity of photoreceptors by facilitating glucose entry into the cells and promoting aerobic glycolysis. Alongside RdCVF, the therapy also delivers RdCVFL (rod-derived cone viability factor long), a variant with antioxidant properties. This helps to reduce oxidative stress in the retina, further preserving the photoreceptors from degeneration.
Another gene therapy clinical trial in progress at the UPMC Vision Institute focuses on X-linked retinitis pigmentosa (XLRP), a severe form of retinal dystrophy caused by mutations in the RPGR gene. This trial is studying a gene therapy designed to correct the underlying genetic defect, potentially stabilizing vision in patients.
"XLRP is a particularly challenging condition, and the gene therapy we're testing offers a promising approach to slow down or even halt the progression of this disease," says Dr. Martel.
In addition, the UPMC Vision Institute is a clinical trial site for RGX-314, a gene therapy designed to treat wet age-related macular degeneration (AMD). Currently, patients with wet AMD require frequent injections of anti-VEGF drugs to manage their condition. However, RGX-314 offers a potentially new approach by inducing the retina to produce a monoclonal antibody that inhibits VEGF on a continuous basis.
"The goal of RGX-314 is to reduce or eliminate the need for ongoing injections by enabling the retina to continuously produce a VEGF inhibitor. This would make for a simpler therapeutic approach and possibly more consistent management of wet AMD," says Dr. Martel.
Participation in these trials highlights the UPMC Vision Institute’s commitment to advancing the field of retinal gene therapy.
"We're at the forefront of exploring these innovative therapies, each targeting different aspects of retinal disease, with the ultimate aim of preserving and improving vision in our patients," says Dr. Martel.
Further Reading
*Disclaimer: Luxturna® is a trademark of Spark Therapeutics.
