The retinal pigment epithelium-specific 65 kilodalton protein (RPE65) is located in the retinal pigment epithelial cells and converts all-trans-retinol to 11-cis-retinol, which subsequently forms the chromophore, 11-cis-retinal, during the visual (retinoid) cycle. These steps are critical in the biological conversion of a photon of light into an electrical signal within the retina. Mutations in the RPE65 gene lead to reduced or absent RPE65 all-trans-retinyl isomerase activity, blocking the visual cycle and resulting in vision loss. Over time, accumulation of toxic precursors leads to the death of retinal pigment epithelial cells, and subsequently to progressive photoreceptor cell death. Individuals with biallelic RPE65 mutation-associated retinal dystrophy exhibit vision loss, including impaired visual function parameters such as visual acuity and visual fields often during childhood or adolescence; this loss of vision ultimately progresses to complete blindness.
Injection of voretigene neparvovec into the subretinal space results in transduction of retinal pigment epithelial cells with a cDNA encoding normal human RPE65 protein (gene augmentation therapy), providing the potential to restore the visual cycle.
Voretigene neparvovec is expected to be taken up by cells through heparin sulphate proteoglycan receptors and be degraded by endogenous proteins and DNA catabolic pathways.
Biodistribution of voretigene neparvovec was evaluated at three months following subretinal administration in non-human primates. The highest levels of vector DNA sequences were detected in intraocular fluids (anterior chamber fluid and vitreous) of vector-injected eyes. Low levels of vector DNA sequences were detected in the optic nerve of the vector-injected eye, optic chiasm, spleen and liver, and sporadically in the stomach and lymph nodes. In one animal administered with voretigene neparvovec at 7.5 × 1011 vg (5 times the recommended per eye dose), vector DNA sequences were detected in colon, duodenum and trachea. Vector DNA sequences were not detected in gonads.
The vector shedding and biodistribution were evaluated in tears from both eyes, serum and whole blood of subjects in the Phase 3 clinical study. In 13/29 (45%) subjects receiving bilateral administrations, voretigene neparvovec vector DNA sequences were detected in tear samples; most of these subjects were negative after the day 1 post-injection visit, however, four of these subjects had positive tear samples beyond the first day, one subject up to day 14 post-second eye injection. Vector DNA sequences were detected in serum in 3/29 (10%) subjects, including two with positive tear samples, and only up to day 3 following each injection. Overall, transient and low levels of vector DNA were detected in tear and occasional serum samples from 14/29 (48%) of subjects in the Phase 3 study.
No pharmacokinetic studies with voretigene neparvovec have been conducted in special populations.
Voretigene neparvovec is injected directly into the eye. Liver and kidney function, cytochrome P450 polymorphisms and ageing are not expected to influence the clinical efficacy or safety of the product. Therefore, no adjustment in dosage is necessary for patients with hepatic or renal impairment.
Ocular histopathology of dog and non-human primate eyes exposed to voretigene neparvovec showed only mild changes, which were mostly related to healing from surgical injury. In an earlier toxicology study, a similar AAV2 vector administered subretinally in dogs at a dose of 10 times the recommended dose resulted in focal retinal toxicity and inflammatory cell infiltrates histologically in regions exposed to the vector. Other findings from voretigene neparvovec non-clinical studies included occasional and isolated inflammatory cells in the retina, with no apparent retinal degeneration. Following a single vector administration, dogs developed antibodies to the AAV2 vector capsid which were absent in naïve non-human primates.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
