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Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence

Nov 13, 2020

Jie Gao, Rehan M Hussain, Christina Y Weng | Clinical Ophthalmology | 13 November 2020 | Vol. 14 | pgs. 3855–3869 |doi: 10.2147/OPTH.S231804


Abstract

Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with Leber congenital amaurosis. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade. RPE65 gene knockout animal models were developed and showed similar diseased phenotypes to their human counterparts. Proof of concept studies were carried out in these animal models using subretinal RPE65 gene replacement therapy, resulting in improvements in various visual function markers including electroretinograms, pupillary light responses, and object avoidance behaviors. Positive results in animal models led to Phase 1 human studies using adeno-associated viral vectors. Results in these initial human studies also showed positive impact on visual function and acceptable safety. A landmark Phase 3 study was then conducted by Spark Therapeutics using a dose of 1.5 x1011 vector genomes after dose-escalation studies confirmed its efficacy and safety. Multi-luminance mobility testing was used to measure the primary efficacy endpoint due to its excellent reliability in detecting the progression of inherited retinal diseases. After the study met its primary endpoint, the Food and Drug Administration approved voretigene neparvovec (Luxturna®) for use in RPE65-associated inherited retinal diseases.


Introduction

Inherited retinal diseases (IRDs) are a heterogenous group of disorders characterized by varying degrees of functional vision loss and associated retinal degenerative changes. For the collective 270 gene mutations that have been identified in association with clinically diagnosed IRDs, the incidence is approximately 1 in 2000.1,2 In most IRDs, the visual loss occurs early and can be profound, resulting in significant disability to the patient. The primary site of degeneration usually involves the photoreceptor and retinal pigment epithelium (RPE) complex. IRDs can be classified as either stationary, such as in congenital stationary night blindness (CSNB), or progressive, such as in retinitis pigmentosa (RP).1 Leber congenital amaurosis (LCA) is one of the most severe types of progressive IRDs, presenting with significant functional vision decline within the first year of life.3,4 This review will provide a brief overview on the RPE65 gene mutation-related dystrophies and focus on the clinical evidence that led to the approval of voretigene neparvovec-rzyl, the first FDA (Food and Drug Administration)-approved gene replacement therapy in the United States and in the European Union.5,6


The RPE65 Gene

Gene Function

The RPE65 gene encodes for a 65 kDa protein located primarily on the smooth endoplasmic reticulum of RPE cells.7 Electroretinograms (ERGs) of biallelic knockout (RPE65 -/-) mice demonstrated diminished or absent waveforms similar to what is seen in humans. Dark-adapted ERGs tended to be worse than light-adapted or flicker ERGs suggesting that rod function is more severely impacted than cone function. In the photoreceptors of these eyes, no detectable rhodopsin was found. In the RPE cells, there was an absence of 11-cis-retinol and an overaccumulation of all-trans-retinol.8 In initial in vitro studies, human cells were transfected with the RPE65 gene along with a LRAT coenzyme gene, followed by exposure to all-trans-retinol. This resulted in decreased all-trans-retinol levels and a dramatic increase in 11-cis-retinol levels, suggesting that the RPE65 protein plays a direct enzymatic role in the isomerization of 11-trans-retinol to 11-cis-retinol.9,10


Other studies suggest that a non-enzymatic role for the RPE65 protein may exist. One study noted that heterozygous (RPE65 +/–) mice have a much larger drop in rod pigment recycling than would be expected compared to wild type (RPE65 +/+) mice if the RPE65 protein was acting solely as an enzyme. This study also showed that when RPE65 -/- mice were given oral 9-cis-retinal supplementation, a small amount of 11-cis-retinal could be detected. The author suggested that other proteins may be involved in the visual cycle pathway that eventually produces 11-cis-retinal. They concluded that the RPE65 protein could either have a dual function as both an isomerase enzyme and a structural protein or as an organizer protein involved in the distribution of retinyl esters within the RPE cells.11 Currently, the exact function of the RPE65 protein is still debated, but what is known is that 11-cis-retinol is converted to 11-cis-retinal which is required by the photoreceptor outer segments in order to combine with opsin and produce the visual pigment that is responsible for detecting light and initiating the phototransduction cascade.7




 

References

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  2. RetNet. Summaries of genes and loci causing retinal diseases. 2-14-2020. [cited May 5, 2020] Available from: https://sph.uth.edu/retnet/sum-dis.htm. Accessed October23, 2020.

  3. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 2004;23(4):306–317. doi: 10.1002/humu.20010

  4. Gu S-M, Thompson DA, Srikumari CR, et al. Mutations in RPE65 cause autosomal recessive childhood–onset severe retinal dystrophy. Nat Genet. 1997;17(2):194–197. doi: 10.1038/ng1097-194

  5. Novartis announces landmark EU approval for one-time gene therapy Luxturna® to restore vision in people with rare inherited retinal disease. November 23, 2018. [cited May 5, 2020] Available from: https://novartis.gcs-web.com/Novartis-announces-landmark-EU-approval-for-one-time-gene-therapy-Luxturna-to-restore-vision-in-people-with-rare-inherited-retinal-disease. Accessed October23, 2020.

  6. LUXTURNA (voretigene neparvovec-rzyl) US full prescribing information. 2017. [cited May 5, 2020] Available from: https://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed October23, 2020.

  7. Thompson DA, Gal A. Vitamin A metabolism in the retinal pigment epithelium: genes, mutations, and diseases. Prog Retin Eye Res. 2003;22(5):683–703. doi: 10.1016/S1350-9462(03)00051-X

  8. Redmond TM, Yu S, Lee E, et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet. 1998;20(4):344–351. doi: 10.1038/3813

  9. Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA. 2005;102(38):13658–13663. doi: 10.1073/pnas.0504167102

  10. Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci USA. 2005;102(35):12413–12418. doi: 10.1073/pnas.0503460102

  11. Van Hooser JP, Aleman TS, He YG, et al. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc Natl Acad Sci USA. 2000;97(15):8623–8628. doi: 10.1073/pnas.150236297

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