What is the mechanism of Voretigene Neparvovec?

Voretigene neparvovec, also known by its brand name Luxturna, is a pioneering gene therapy approved for the treatment of inherited retinal dystrophy caused by mutations in the RPE65 gene. This groundbreaking therapy offers hope to individuals suffering from conditions such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), which lead to progressive vision loss and, in many cases, complete blindness.

The mechanism of voretigene neparvovec revolves around the delivery of a functional copy of the RPE65 gene to retinal cells. The RPE65 gene encodes an enzyme essential for the visual cycle, a biochemical process that converts light into electrical signals in the retina, enabling vision. In patients with mutations in the RPE65 gene, this critical enzyme is either absent or non-functional, disrupting the visual cycle and leading to the degeneration of photoreceptor cells.

To address this genetic defect, voretigene neparvovec employs a gene therapy vector based on adeno-associated virus serotype 2 (AAV2). The AAV2 vector is chosen for its safety profile and ability to effectively transduce retinal cells. The therapeutic gene is packaged within the AAV2 vector, which is then administered directly into the subretinal space of the eye through a surgical procedure. This targeted delivery ensures that the gene reaches the retinal pigment epithelium (RPE) cells, where it can exert its therapeutic effect.

Once delivered, the AAV2 vector carrying the functional RPE65 gene transduces the RPE cells. The transduced cells begin to produce the RPE65 enzyme, thereby restoring the visual cycle. The restored visual cycle facilitates the conversion of 11-cis-retinal to all-trans-retinal, a crucial step in the phototransduction pathway. As a result, the photoreceptor cells can once again respond to light stimuli, improving visual function.

The clinical effectiveness of voretigene neparvovec has been demonstrated in several studies. Patients treated with this gene therapy have shown significant improvements in visual acuity, navigational ability in low light, and overall quality of life. These positive outcomes underscore the transformative potential of gene therapy in treating inherited retinal diseases.

In summary, voretigene neparvovec operates through a well-defined mechanism aimed at correcting the underlying genetic defect in RPE65-associated retinal dystrophy. By delivering a functional copy of the RPE65 gene to the retinal cells, this therapy restores the visual cycle, improves retinal function, and offers a new lease on life for individuals affected by these debilitating conditions. This innovative approach marks a significant milestone in the field of gene therapy and ophthalmology, paving the way for future advancements in the treatment of genetic disorders.