The RPE65 gene is essential for healthy vision. It codes for a protein located in the retinal pigment epithelium (RPE), a cell layer at the back of the eye. Mutations in the RPE65 gene cause severe inherited blindness, often early in life. These disruptions impair the visual process, affecting how the eye converts light into brain signals.
RPE65’s Function in the Eye
The RPE65 protein functions within retinal pigment epithelium cells. It acts as a retinoid isomerase enzyme. This enzyme is responsible for a step in the visual cycle (also called the retinoid or vitamin A cycle). This multi-step cycle allows retinal photoreceptor cells to continuously detect light.
When light strikes retinal pigments, 11-cis retinal converts to all-trans retinal. RPE65 then converts all-trans retinal into 11-cis retinol. Other enzymes transform 11-cis retinol back into 11-cis retinal, continuing the visual cycle and enabling repeated light capture. Without functional RPE65, this conversion is disrupted, leading to all-trans retinal buildup and reduced 11-cis retinal, impairing the visual cycle.
Vision Conditions Linked to RPE65
RPE65 gene mutations cause inherited retinal diseases, mainly Leber Congenital Amaurosis (LCA) type 2 and early-onset Retinitis Pigmentosa (RP). These conditions involve progressive degeneration of retinal photoreceptors. LCA is a severe retinal dystrophy, usually appearing at birth or within the first year, with symptoms like poor visual behavior and nystagmus. Patients with RPE65-associated LCA often have severely reduced visual acuity, from 20/200 to light perception only.
Early-onset Retinitis Pigmentosa, also linked to RPE65 mutations, resembles LCA but can appear later, between one and five years of age. A common initial symptom for both conditions is night blindness, or difficulty seeing in dim light, often observed in early childhood. Over time, patients experience progressive loss of visual field and acuity, with many becoming legally blind by middle age. Severity and progression vary.
Gene Therapy for RPE65-Related Conditions
Gene therapy offers a significant advancement for RPE65-related retinal dystrophies. The first FDA-approved gene therapy is voretigene neparvovec (Luxturna). This therapy delivers a functional RPE65 gene copy to affected retinal cells.
Luxturna uses an adeno-associated virus (AAV) vector to transport the healthy RPE65 gene into retinal pigment epithelium cells. This modified AAV vector does not cause disease but effectively delivers genetic material. The therapy is administered via subretinal injection, a surgical procedure delivering the agent directly underneath the retina.
Clinical trials show voretigene neparvovec improves light sensitivity and functional vision for patients with RPE65-mediated retinal dystrophy. Patients demonstrate improved ability to navigate mobility courses in various lighting conditions and increased full-field light sensitivity. While it does not restore normal vision, the treatment significantly improves visual function and prevents further decline for individuals with viable retinal cells.