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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

An algorithm for gene therapy in RPE65-LCA. Diagnostic workup is followed by clinical staging for severity of retinal degeneration. Photoreceptor life expectancy from time of initial mapping can then be calculated using the delayed exponential model of the disease. Simple or more complex strategies can then proceed with targeting of specific regions of retina proven to have photoreceptor integrity. Neuroprotection can be initiated as early as the diagnosis is made. See text for more details.
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Figure 0004: An algorithm for gene therapy in RPE65-LCA. Diagnostic workup is followed by clinical staging for severity of retinal degeneration. Photoreceptor life expectancy from time of initial mapping can then be calculated using the delayed exponential model of the disease. Simple or more complex strategies can then proceed with targeting of specific regions of retina proven to have photoreceptor integrity. Neuroprotection can be initiated as early as the diagnosis is made. See text for more details.

Mentions: A sequence from clinical diagnosis to staging to treatment is illustrated (Figure 4). In the clinical staging column, there is a photoreceptor life expectancy graph. The horizontal axis is the time (years) since degeneration phase onset; ONL fraction remaining is plotted vertically in log units. The photoreceptor life expectancy for each stage (labeled below horizontal axis) is based on the patient’s average ONL fraction at time of imaging (marked by circle) until the ‘end-of-life’ criterion (−1 log unit ONL fraction, which is 10% of normal mean). A relatively simple gene transfer strategy with a series of single uniocular subretinal injections over years is shown. More complex strategies with two injections per eye and binocular treatments are possible. Initial administration targets the superior retina, as shown in the schematic of the fundus. Hypothetical outcomes are illustrated for each of three disease severities (see Staging above). Predicted visual improvement (at peak response) is shown as a square on a visual field map. After an interval determined by disease severity stage and the expected time to peak improvement, the nasal retina is treated. Treatment of the temporal retina could follow after a further interval, thereby providing a substantial total area of visual field that would otherwise be lost.


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)

An algorithm for gene therapy in RPE65-LCA. Diagnostic workup is followed by clinical staging for severity of retinal degeneration. Photoreceptor life expectancy from time of initial mapping can then be calculated using the delayed exponential model of the disease. Simple or more complex strategies can then proceed with targeting of specific regions of retina proven to have photoreceptor integrity. Neuroprotection can be initiated as early as the diagnosis is made. See text for more details.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0004: An algorithm for gene therapy in RPE65-LCA. Diagnostic workup is followed by clinical staging for severity of retinal degeneration. Photoreceptor life expectancy from time of initial mapping can then be calculated using the delayed exponential model of the disease. Simple or more complex strategies can then proceed with targeting of specific regions of retina proven to have photoreceptor integrity. Neuroprotection can be initiated as early as the diagnosis is made. See text for more details.
Mentions: A sequence from clinical diagnosis to staging to treatment is illustrated (Figure 4). In the clinical staging column, there is a photoreceptor life expectancy graph. The horizontal axis is the time (years) since degeneration phase onset; ONL fraction remaining is plotted vertically in log units. The photoreceptor life expectancy for each stage (labeled below horizontal axis) is based on the patient’s average ONL fraction at time of imaging (marked by circle) until the ‘end-of-life’ criterion (−1 log unit ONL fraction, which is 10% of normal mean). A relatively simple gene transfer strategy with a series of single uniocular subretinal injections over years is shown. More complex strategies with two injections per eye and binocular treatments are possible. Initial administration targets the superior retina, as shown in the schematic of the fundus. Hypothetical outcomes are illustrated for each of three disease severities (see Staging above). Predicted visual improvement (at peak response) is shown as a square on a visual field map. After an interval determined by disease severity stage and the expected time to peak improvement, the nasal retina is treated. Treatment of the temporal retina could follow after a further interval, thereby providing a substantial total area of visual field that would otherwise be lost.

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