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

Jacobson SG, Cideciyan AV, Aguirre GD, Roman AJ, Sumaroka A, Hauswirth WW, Palczewski K - Expert Opin Orphan Drugs (2015)

Bottom Line: This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances.Logical next steps to advance the clinical value of the therapeutics are suggested.Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space.

View Article: PubMed Central - PubMed

Affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.

ABSTRACT

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention.

No MeSH data available.


Related in: MedlinePlus

RPE65 and the retinoid cycle. Schematic of a retinal pigment epithelial (RPE) cell and a photoreceptor cell outer segment with the flow of retinoids within and between the two different cells. There are intracellular and extracellular retinoid-binding proteins (such as CRALBP, CRBP1, IRBP). The retinoid isomerase, RPE65 (top center of the figure), the retinoid isomerase, is deficient in a form of LCA. See text for more details.
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Figure 0001: RPE65 and the retinoid cycle. Schematic of a retinal pigment epithelial (RPE) cell and a photoreceptor cell outer segment with the flow of retinoids within and between the two different cells. There are intracellular and extracellular retinoid-binding proteins (such as CRALBP, CRBP1, IRBP). The retinoid isomerase, RPE65 (top center of the figure), the retinoid isomerase, is deficient in a form of LCA. See text for more details.

Mentions: Visual pigments in rod and cone photoreceptor cells detect light because they have the covalently linked light-sensitive chromophore, 11-cis-retinal. Light causes photoisomerization of this chromophore and its release as all-trans-retinal. Metabolic transformation of spent all-trans-retinal back to its light-sensitive form, 11-cis-retinal, is achieved by a series of transport and enzymatic processes termed the retinoid cycle. Combining recycled 11-cis-retinal with opsins to form visual pigments completes chromophore regeneration and permits phototransduction and visual perception to continue 14, 15, 16, 17, 18. One of the key enzymes of the retinoid cycle is retinoid isomerase, which is encoded by the RPE65 gene (Figure 1). Deficiency of RPE65 leads to visual loss in human LCA. This visual disturbance is due not only to an inadequate supply of 11-cis-retinal but also to varying degrees of retinal degeneration 7, 19, 20, 21, 22.


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

Jacobson SG, Cideciyan AV, Aguirre GD, Roman AJ, Sumaroka A, Hauswirth WW, Palczewski K - Expert Opin Orphan Drugs (2015)

RPE65 and the retinoid cycle. Schematic of a retinal pigment epithelial (RPE) cell and a photoreceptor cell outer segment with the flow of retinoids within and between the two different cells. There are intracellular and extracellular retinoid-binding proteins (such as CRALBP, CRBP1, IRBP). The retinoid isomerase, RPE65 (top center of the figure), the retinoid isomerase, is deficient in a form of LCA. See text for more details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487613&req=5

Figure 0001: RPE65 and the retinoid cycle. Schematic of a retinal pigment epithelial (RPE) cell and a photoreceptor cell outer segment with the flow of retinoids within and between the two different cells. There are intracellular and extracellular retinoid-binding proteins (such as CRALBP, CRBP1, IRBP). The retinoid isomerase, RPE65 (top center of the figure), the retinoid isomerase, is deficient in a form of LCA. See text for more details.
Mentions: Visual pigments in rod and cone photoreceptor cells detect light because they have the covalently linked light-sensitive chromophore, 11-cis-retinal. Light causes photoisomerization of this chromophore and its release as all-trans-retinal. Metabolic transformation of spent all-trans-retinal back to its light-sensitive form, 11-cis-retinal, is achieved by a series of transport and enzymatic processes termed the retinoid cycle. Combining recycled 11-cis-retinal with opsins to form visual pigments completes chromophore regeneration and permits phototransduction and visual perception to continue 14, 15, 16, 17, 18. One of the key enzymes of the retinoid cycle is retinoid isomerase, which is encoded by the RPE65 gene (Figure 1). Deficiency of RPE65 leads to visual loss in human LCA. This visual disturbance is due not only to an inadequate supply of 11-cis-retinal but also to varying degrees of retinal degeneration 7, 19, 20, 21, 22.

Bottom Line: This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances.Logical next steps to advance the clinical value of the therapeutics are suggested.Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space.

View Article: PubMed Central - PubMed

Affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.

ABSTRACT

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention.

No MeSH data available.


Related in: MedlinePlus