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  • Review Article
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Macular degeneration: recent advances and therapeutic opportunities

Nature Reviews Neuroscience volume 7, pages 860–872 (2006)Cite this article

Key Points

  • The macula is the central retinal region specialized for high acuity vision.

  • The retina has the highest oxygen consumption of any tissue in the body and together with the underlying retinal pigment epithelium (RPE) lives a metabolically precarious existence.

  • The retina is the only region of the human nervous system that can be observed directly. Two new, non-invasive imaging technologies, optical coherence tomography (OCT) and confocal scanning laser ophthalmoscopy (cSLO), allow the clinician to view the retina with nearly cellular resolution.

  • Genes for all of the main early-onset types of macular degeneration have been identified, and they reveal a role for the following structures or processes in macular disease: anion flux in the RPE; retinoid cycling and the production of a phototoxic retinoid-derived side product (A2E); the sub-RPE extracellular matrix; pro-angiogenic signalling; and long-chain fatty acid synthesis.

  • Animal models implicate oxidative, and in particular photo-oxidative, damage and immune system defects in the pathogenesis of macular degeneration.

  • Sub-RPE deposits are associated with age-related macular degeneration (AMD). The protein composition of these deposits and the results of experiments using knockout mice implicate the immune response in the pathogenesis of AMD.

  • Three loci with large effects on AMD risk have been identified. Two of these loci code for regulators of the complement cascade (complement factors B and H), directly implicating misregulation of the complement cascade in AMD.

  • Current therapies for AMD focus on blocking the growth of new blood vessels from the choroid into the retina (choroidal neovascularization). A major challenge for the future will be to develop therapies that target earlier stages in the progression of macular disease.

Abstract

The central retina mediates high acuity vision, and its progressive dysfunction due to macular degeneration is the leading cause of visual disability among adults in industrialized societies. Here, we summarize recent progress in understanding the pathophysiology of macular degeneration and the implications of this new knowledge for treatment and prevention. The past decade has witnessed remarkable advances in this field, including the development of new, non-invasive retinal imaging technologies, the development of animal models for macular disease, and the isolation of many of the genes responsible for both early- and late-onset macular diseases. These advances have set the stage for the development of effective mechanism-based therapies.

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Figure 1: The structure of the human eye and retina.
Figure 2: The central retina as seen through the ophthalmoscope.
Figure 3: The retinoid cycle and A2E.
Figure 4: The retinal pigment epithelium, Bruch's membrane and the choroid.
Figure 5: Location and composition of drusen.
Figure 6: The alternative complement pathway and the roles of complement factors B and H.

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Acknowledgements

The authors thank the following colleagues for permission to reproduce images: R. Cucu (Box 1c); G. Hageman (Fig. 5a–c); F. Holz (Box 1b); L. Johnson (Fig. 5d); R. Lewis (Fig. 2a,c); J. Sparrow (Fig. 3b); E. Stone (Fig. 2b; Box 1a); and H. Sun (Fig. 4a). The authors are supported by the National Institutes of Health (National Eye Institute) and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Amir Rattner & Jeremy Nathans

  2. Department of Neuroscience, Department of Ophthalmology, and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jeremy Nathans

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Correspondence to Jeremy Nathans.

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Jeremy Nathans is a paid consultant for the Ophthalmology Group at the Novartis Research Institute.

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DATABASES

OMIM

Sorsby's fundus dystrophy

Marfan syndrome

malattia leventinese

vitelliform macular dystrophy

FURTHER INFORMATION

GenBank database

Glossary

Metalloproteinase

A proteinase that has a metal ion at its active site.

Druse/drusen

Discrete sub-retinal pigment epithelium deposits composed of a complex mixture of lipid and protein. From German, meaning 'rock' or 'geode'.

Fundus

The posterior region of the eye, including the retina, retinal pigment epithelium and choroid.

Hypercholesterolemia

Elevated serum cholesterol levels.

Confocal scanning laser ophthalmoscopy

(cSLO). A non-invasive technique for fundus examination that produces en face images of the retina at high spatial resolution.

Logarithm of the odds (LOD) score

The standard statistical test for genetic linkage, whereby the likelihood of bone fide linkage is compared to the probability that the data reflect a chance association.

Single nucleotide polymorphism

(SNP). One of the most common genetic variations in humans. It occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (adenine, guanine or cytosine).

Haplotype

Clustered DNA sequence variants that were present together on a common ancestral chromosome. Because of their close proximity they are generally inherited together and serve to define the ancestral chromosomal region.

Major histocompatibility complex

(MHC). There are two classes of MHC molecules. MHC class I molecules are found on the surface of most cells and present proteins that are generated in the cytosol to T lymphocytes. MHC class II molecules are expressed only on the surface of activated antigen-presenting cells, and they present peptides that have been degraded in cellular vesicles to T cells.

Hyperlipidemia

Elevated serum lipid levels.

Optical coherence tomography

(OCT). A non-invasive technique for fundus examination that produces cross-sectional images of the retina, retinal pigment epithelium and choroid.

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Rattner, A., Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nat Rev Neurosci 7, 860–872 (2006). https://doi.org/10.1038/nrn2007

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