Gene therapy is now available at Mayo Clinic as a potential treatment for previously incurable complex diseases. Voretigene neparvovec-rzyl, the first prescription retinal gene therapy, offers hope for eligible patients with mutations in both copies of the RPE65 gene, potentially restoring the visual cycle and improving functional vision.
A Game Changer for Ophthalmology
"This is a game changer, not only for ophthalmology but also for all of medicine," says Dr. Brittni A. Scruggs, an ophthalmologist at Mayo Clinic. The availability of voretigene neparvovec-rzyl marks a significant advancement in treating inherited retinal diseases (IRDs). This treatment sets the stage for other gene therapies, representing an exciting innovation in the field.
Voretigene neparvovec-rzyl is indicated for patients with Leber congenital amaurosis due to mutations in both copies of the RPE65 gene, who also have sufficient viable cells remaining in the outer retina. Patients with these mutations often experience night blindness (nyctalopia), loss of contrast sensitivity or color vision, loss of central or peripheral vision, impaired dark adaptation, and nystagmus.
Clinical Trial Evidence
A phase 3 clinical trial published in The Lancet in 2017 demonstrated that voretigene neparvovec-rzyl improved functional vision, enhancing patients' ability to perform daily life activities. The randomized, controlled trial included participants with a confirmed genetic diagnosis of biallelic RPE65 mutation, sufficient viable retina, and the ability to perform standardized multiluminance mobility testing (MLMT). The study found that vector administration in both eyes led to clinically meaningful and statistically significant improvements in the ability to navigate independently in low to moderate light conditions, as shown by change in MLMT score in the intervention group compared with that in controls.
Mechanism of Action
"We inject voretigene neparvovec-rzyl under the retina, making a localized retinal detachment. This adeno-associated virus solution infects cells — specifically, the retinal pigment epithelium — that are still present but are not functioning," explains Dr. Scruggs. "The virus works quickly, allowing the visual cycle to continue."
Genetic Testing and Diagnosis
RPE65 is one of over 300 genes that can cause IRDs. Confirming a patient's specific gene mutation through genetic testing is the first step in determining if this gene therapy is a suitable treatment option. According to Dr. Raymond Iezzi Jr., determining the exact genetic cause of a patient's disease allows for accurate diagnosis, prognosis, and counseling on clinical trial opportunities and vision rehabilitation strategies.
Collaborative Care Model
Mayo Clinic employs a collaborative approach, with medical geneticists and genetic counselors working closely with patients. Dr. Lisa A. Schimmenti emphasizes that genetic testing is offered to individuals with suspected IRDs within a shared decision-making model. The team provides individuals and families with the knowledge needed to make informed decisions regarding genetic testing, and results are returned in the context of genetic counseling to understand the impact of their results and their eligibility for gene therapy.
Ongoing Research
Mayo Clinic is actively involved in clinical trials evaluating treatments for various retinal conditions, including Stargardt disease, retinal dystrophies associated with rare disease-causing genetic variants, retinitis pigmentosa, and X-linked retinitis pigmentosa.
Dr. Scruggs notes that while some patients with IRDs may not yet have a clinical trial or treatment option, the priority remains optimizing their quality of vision and quality of life with available resources. For those who are candidates for voretigene neparvovec-rzyl, Mayo Clinic is excited to be at the forefront of providing cutting-edge gene therapy, offering patients a more vibrant view of the world.
