Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy

Abstract

Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly expressed in the retinal pigment epithelium where it encodes the retinoid isomerase enzyme essential for the production of chromophore which forms the visual pigment in rod and cone photoreceptors of the retina. Congenital loss of chromophore production due to RPE65-deficiency together with progressive photoreceptor degeneration cause severe and progressive loss of vision. RPE65-associated LCA recently gained recognition outside of specialty ophthalmic circles due to early success achieved by three clinical trials of gene therapy using recombinant adeno-associated virus (AAV) vectors. The trials were built on multitude of basic, pre-clinical and clinical research defining the pathophysiology of the disease in human subjects and animal models, and demonstrating the proof-of-concept of gene (augmentation) therapy. Substantial gains in visual function of clinical trial participants provided evidence for physiologically relevant biological activity resulting from a newly introduced gene. This article reviews the current knowledge on retinal degeneration and visual dysfunction in animal models and human patients with RPE65 disease, and examines the consequences of gene therapy in terms of improvement of vision reported.

TULP1Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

“…The TULP1-RD result showed a resemblance to that previously measured in foveas of RPE65-LCA 21,57 where the pathophysiology is thought to involve a substantial reduction in chromophore production. 71 There was also similarity to the results measured in extrafoveal rods of CSNB caused by NYX or CACNA1F mutations. 58 The pathophysiology of the latter two diseases is thought to localize at the synapses between photoreceptors and bipolar cells.…”

TULP1Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

“…The TULP1-RD result showed a resemblance to that previously measured in foveas of RPE65-LCA 21,57 where the pathophysiology is thought to involve a substantial reduction in chromophore production. 71 There was also similarity to the results measured in extrafoveal rods of CSNB caused by NYX or CACNA1F mutations. 58 The pathophysiology of the latter two diseases is thought to localize at the synapses between photoreceptors and bipolar cells.…”

Improvement in vision: a new goal for treatment of hereditary retinal degenerations

“…Subretinal gene therapy using AAV, adenovirus (Ad) and lentiviral vectors was also performed in the Rpe65 −/− (knockout) mouse model as well as the naturally occurring Rpe65 rd12 mouse model. For the most part, there was improved retinal function ( Figure 2B ) with supporting immunohistochemistry, rhodopsin biochemistry and cortical activity studies [7] .…”

“…This proof-of-concept experiment was confirmed and extended in many additional studies. Visual function improvements were recorded at retinal, subcortical and cortical levels, and there were concordant biochemical, morphological and immunohistochemical observations 7 , 39 , 40 .…”

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

“…The unexpected bilateral improvement in vision observed in REVERSE is in contrast to the results obtained in other gene therapies targeting photoreceptors or the retinal pigment epithelium with a surgical subretinal injection of the viral vector (7,25). However, an improvement in visual function in the untreated eye following unilateral intravitreal administration of the viral vector has been demonstrated in other gene therapy trials for LHON (26)(27)(28)(29).…”

TULP1Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

“…The TULP1-RD result showed a resemblance to that previously measured in foveas of RPE65-LCA 21,57 where the pathophysiology is thought to involve a substantial reduction in chromophore production. 71 There was also similarity to the results measured in extrafoveal rods of CSNB caused by NYX or CACNA1F mutations. 58 The pathophysiology of the latter two diseases is thought to localize at the synapses between photoreceptors and bipolar cells.…”

Improvement in vision: a new goal for treatment of hereditary retinal degenerations

“…Subretinal gene therapy using AAV, adenovirus (Ad) and lentiviral vectors was also performed in the Rpe65 −/− (knockout) mouse model as well as the naturally occurring Rpe65 rd12 mouse model. For the most part, there was improved retinal function ( Figure 2B ) with supporting immunohistochemistry, rhodopsin biochemistry and cortical activity studies [7] .…”

“…This proof-of-concept experiment was confirmed and extended in many additional studies. Visual function improvements were recorded at retinal, subcortical and cortical levels, and there were concordant biochemical, morphological and immunohistochemical observations 7 , 39 , 40 .…”

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

“…The unexpected bilateral improvement in vision observed in REVERSE is in contrast to the results obtained in other gene therapies targeting photoreceptors or the retinal pigment epithelium with a surgical subretinal injection of the viral vector (7,25). However, an improvement in visual function in the untreated eye following unilateral intravitreal administration of the viral vector has been demonstrated in other gene therapy trials for LHON (26)(27)(28)(29).…”

TULP1Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

“…The TULP1-RD result showed a resemblance to that previously measured in foveas of RPE65-LCA 21,57 where the pathophysiology is thought to involve a substantial reduction in chromophore production. 71 There was also similarity to the results measured in extrafoveal rods of CSNB caused by NYX or CACNA1F mutations. 58 The pathophysiology of the latter two diseases is thought to localize at the synapses between photoreceptors and bipolar cells.…”

Improvement in vision: a new goal for treatment of hereditary retinal degenerations

“…Subretinal gene therapy using AAV, adenovirus (Ad) and lentiviral vectors was also performed in the Rpe65 −/− (knockout) mouse model as well as the naturally occurring Rpe65 rd12 mouse model. For the most part, there was improved retinal function ( Figure 2B ) with supporting immunohistochemistry, rhodopsin biochemistry and cortical activity studies [7] .…”

“…This proof-of-concept experiment was confirmed and extended in many additional studies. Visual function improvements were recorded at retinal, subcortical and cortical levels, and there were concordant biochemical, morphological and immunohistochemical observations 7 , 39 , 40 .…”

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

“…The unexpected bilateral improvement in vision observed in REVERSE is in contrast to the results obtained in other gene therapies targeting photoreceptors or the retinal pigment epithelium with a surgical subretinal injection of the viral vector (7,25). However, an improvement in visual function in the untreated eye following unilateral intravitreal administration of the viral vector has been demonstrated in other gene therapy trials for LHON (26)(27)(28)(29).…”