Exploring New Frontiers in Retinal Disease

Achieving our mission starts with a fundamental understanding of unmet needs in the retinal landscape. By identifying gaps and researching uncharted territory, we adapt our mission to fit the needs of the community.

Geographic Atrophy

Pathophysiology

Age-related macular degeneration (AMD) is the most widespread cause of irreversible loss of visual function, affecting millions of individuals in the United States.1

The macula is a small area in the central portion of the retina responsible for central vision. As AMD progresses, the loss of retinal cells and the underlying blood vessels in the macula results in marked thinning and/or atrophy of retinal tissue. Geographic atrophy (GA), this advanced stage of AMD, can lead to irreversible loss of vision.2

Healthy Retina
Geographic Atrophy
Image source: Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. Retina. 2017;37(5):819-835.

Diagnosis

GA lesions can be identified using a variety of retinal imaging techniques. On fundus autofluorescence, GA lesions appear as sharply defined areas of retinal pigment epithelium hypopigmentation, with the underlying choroidal vessels clearly visible.2

Fundus Autofluorescence

On fundus autofluorescence, GA lesions appear as areas of decreased autofluorescence caused by loss of retinal pigment epithelium cells containing intrinsic fluorophores such as lipofuscin.2

Fundus Autofluorescence

On fundus autofluorescence, GA lesions appear as areas of decreased autofluorescence caused by loss of retinal pigment epithelium cells containing intrinsic fluorophores such as lipofuscin.2

Fluorescein angiography

On fluorescein angiography, GA lesions appear as well-defined areas of early coloring called "window defects." These are created when retinal pigment epithelium loss enhances the appearance of underlying choroidal vasculature perfused with fluorescein dye.2

Fluorescein angiography

On fluorescein angiography, GA lesions appear as well-defined areas of early coloring called "window defects." These are created when retinal pigment epithelium loss enhances the appearance of underlying choroidal vasculature perfused with fluorescein dye.2

Optical Coherence Tomography

On Optical Coherence Tomography (OCT), GA lesions can usually be identified by the loss of outer retinal layers corresponding to the photoreceptors and retinal pigment epithelium.2

Optical Coherence Tomography

On Optical Coherence Tomography (OCT), GA lesions can usually be identified by the loss of outer retinal layers corresponding to the photoreceptors and retinal pigment epithelium.2

Natural History

A pair of global, prospective, noninterventional, observational studies (Proxima A and B) characterized the visual function decline associated with progression of GA secondary to AMD.3

In both studies, untreated GA secondary to AMD showed a continuous and marked increase in GA lesion size over a 2-year follow-up period.3 At the same time, visual function showed a continuous and marked deterioration.3

The goal of emerging treatments for GA secondary to AMD is to slow the natural progression of lesion growth in order to preserve visual function for as long as possible.

Mean change in GA lesion size over 2 years
Mean change best-corrected visual acuity over 2 years
Image adapted from: Holekamp N, Wykoff CC, Schmitz-Valckenberg S, et al. Ophthalmology. 2020;127(6):769-783.
References: 1. Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844-51. 2. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390. 3. Holekamp N, Wykoff CC, Schmitz-Valckenberg S, et al. Natural history of geographic atrophy secondary to age-related macular degeneration: results from the prospective Proxima A and B clinical trials. Ophthalmology. 2020;127(6):769-783.

Stargardt Disease

Pathophysiology

Stargardt disease is the most common form of inherited macular degeneration, with an estimated prevalence of between 1 in 8,000 and 1 in 10,000 individuals.1

The most common form of Stargardt disease is the autosomal recessive form. Autosomal recessive Stargardt disease is caused by mutations in the ABCA4 gene. Affected individuals typically present with bilateral central macular atrophy during childhood, adolescence or early adulthood, which leads to vision loss as affected individuals age and the disease progresses.1

One Carrier Parent
Two Carrier Parents
Image adapted from: Holekamp N, Wykoff CC, Schmitz-Valckenberg S, et al. Ophthalmology. 2020;127(6):769-783.

Diagnosis

Due to the large number (>900) of genetic variants in the ABCA4 gene that lead to Stargardt disease, the condition is usually different in its presentation.1

On color fundus photography, Stargardt disease lesions typically appear as yellowish-white retinal flecks with concomitant macular atrophy, although these flecks may be slow to develop, resulting in delayed diagnosis.1 On fundus autofluorescence, Stargardt disease lesions appear as flecks of both increased and decreased autofluorescence with central macular hypoautofluorescence surrounded by a "halo" of greater fluorescence signal.1

Natural History

The multicenter Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies have been conducted to characterize the natural history of Stargardt disease.2

In eyes with a confirmed diagnosis of Stargardt disease, atrophic lesions show slow but continuous growth over 12 months, with large lesions showing a somewhat faster rate of growth than small or intermediate-sized lesions.3

Image courtesy of SriniVas R. Sadda, MD.
References: 1. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017;101(1):25-30. 2. Strauss RW, Ho A, Muñoz B, et al. The natural history of the progression of atrophy secondary to Stargardt disease (ProgStar) studies: design and baseline characteristics: ProgStar Report No. 1. Ophthalmology. 2016;123(4):817-828. 3. Strauss RW, Kong X, Ho A, et al. Progression of Stargardt disease as determined by fundus autofluorescence over a 12-month period: ProgStar Report No. 11. JAMA Ophthalmol. 2019;137(10):1134-1145.

Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are a genetically heterogeneous group of diseases, with hundreds (>260) of disease-causing genes identified to date.1

Despite their heterogeneity, IRDs share a progressive and visually debilitating clinical course caused by dysfunction in genes that are critical to phototransduction and maintenance of retinal tissue homeostasis.1

Many IRDs are rare and/or orphan conditions, with limited resources allocated to developing treatments capable of modifying the rate of disease progression and/or restoring lost visual function.1

IRDs where Iveric Bio has an ongoing research focus include:
Rhodopsin-Mediated, Autosomal Dominant Retinitis Pigmentosa
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Leber Congenital Amaurosis Type 10
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BEST1-Related IRDs
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USH2A-Related IRDs
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Rhodopsin-Mediated, Autosomal Dominant Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a family of IRDs characterized by cellular abnormalities in rod and, later, cone photoreceptors, which undergo apoptosis, leading to progressive loss of visual function.2

 

Mutations in dozens of different genes have been linked to RP; over a quarter of RP cases can be attributed to mutations in the RHO gene, which encodes rhodopsin, a component of the phototransduction pathway.2

Leber Congenital Amaurosis Type 10

Leber congenital amaurosis (LCA) is the most severe and earliest-onset IRD currently known. Most children with LCA present with severe and early loss of visual function, slow or near-absent pupillary responses, and severely depressed or undetectable neuroretinal electrical activity on an electroretinogram.3 Mutations in at least 22 different genes have been identified as causes of LCA, although up to half of LCA patients do not have a confirmed genetic cause.3 The most common type of LCA is LCA10, which is caused by mutations in the CEP290 gene.

BEST1-Related IRDs

The BEST1 gene encodes for a multifunctional protein known as bestrophin-1, or BEST1, which regulates chemical transport and signaling in RPE cells and helps maintain homeostasis in the subretinal space, the space between the photoreceptors and the RPE. The most common BEST1-related IRD is Best disease, which is generally autosomal dominant and generally affects individuals in both eyes. In Best disease, the lack of functional BEST1 protein results in the formation of egg yolk-like lesions in the macula that, over time, progress to macular atrophy and permanent loss of vision. In addition, because there are over 200 known mutations in the BEST1 gene, there are other BEST1-related IRDs being studied, including autosomal recessive forms.

USH2A-Related IRDs

The USH2A gene encodes for a protein called usherin. Usherin is believed to be important in the development and maintenance of cells in the retina and the inner ear. There are two principal IRDs associated with mutations in the USH2A gene: Usher syndrome type 2A and USH2A-associated nonsyndromatic autosomal recessive retinitis pigmentosa (RP). Usher syndrome type 2A is an autosomal recessive syndrome characterized by hearing loss from birth and progressive vision loss, due to RP, that begins in adolescence or adulthood. USH2A-associated nonsyndromatic autosomal recessive RP is a genetic condition that manifests as vision loss without associated hearing loss.

References: 1. Duncan JL, Pierce EA, Laster AM, et al. Inherited retinal degenerations: current landscape and knowledge gaps. Transl Vis Sci Technol. 2018;7(4):6. 2. Ferrari S, Di Iorio E, Barbaro V, et al. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011;12(4):238-249. 3. Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015;3(2):112-124. 4. Budiene B, Liutkeviciene R, Zaliuniene D. Best vitelliform macular dystrophy: literature review. Central Eur J Med. 2014;9(6):784-795. 5. Mathur P, Yang J. Usher syndrome: hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta. 2015;1852(3):406-420.
Information for Patients
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