Two recent genetic discoveries may offer hope for patients with advanced AMD

The discovery of a gene for North Carolina macular dystrophy, PRDM13, and transplantation of induced pluripotent stem cells (iPSCs)-derived retinal cells show promise to restoring vision to patients with advanced AMD.

Take-home message: The discovery of a gene for North Carolina macular dystrophy, PRDM13, and transplantation of induced pluripotent stem cells (iPSCs)-derived retinal cells show promise to restoring vision to patients with advanced AMD.

Iowa City, IA-With age-related macular degeneration (AMD) as one of the major medical problems facing the developed world, this retina disease is expected to affect one in three persons over the age of 75 years in the United States by 2025.

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Therefore, treatment options must improve if clinicians are to address this disease adequately, according to Edwin Stone, MD, PhD.

Because more than 50% of AMD is genetic, the chances are good researchers eventually will understand the disease’s mechanism-thus allowing specific treatments to be developed and delivered to high-risk patients before irreversible disease develops.

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Recent inroads into AMD-such as the discovery of a gene for North Carolina macular dystrophy, PRDM13, and transplantation of induced pluripotent stem cells (iPSCs)-derived retinal cells-may restore vision to patients with advanced disease. Dr. Stone discussed these two important research developments.

Dr. Stone is professor of ophthalmology, Department of Ophthalmology and Visual Sciences, Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City.

Genetic association


Genetic association

CFH and C2/CFB are two of the genetic loci that have the greatest statistical association with AMD, Dr. Stone explained. These loci encode members of the complement cascade, which has focused a great deal of attention on the complement pathway.

Research has shown clearly that the membrane attack complex surrounds the choriocapillaris, Dr. Stone said.

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The membrane attack complex consists of choroidal deposits that precede drusen formation in most eyes with AMD. However, they are more abundant in eyes with high-risk complement H genotypes.

Dr. Stone shared some data from a study of the Iowa AMD complex cohort that indicated some features of AMD genetics are often overlooked.

When 927 AMD patients were compared with 305 patients with normal eyes, all of whom were aged in the low-to-mid 80s, there was a strong association seen with the ARMS2, CFH, and C2/CFB genes. However, when eyes with neovascular AMD were compared with those with dry AMD, no such association was seen.

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“Thus, these loci do not contribute to choroidal neovascularization [CNV] directly, nor are they good predictors of which specific AMD patients will develop CNV,” Dr. Stone said. “These triggers remain to be discovered.”

The relative risks of the strongest AMD loci are relatively modest compared with disease-causing mutations in some Mendelian macular diseases, such as autosomal recessive/dominant Stargardt disease, Best disease, and North Carolina macular dystrophy, among others, he explained.

Other factors add risk


Genetic factors add to risk

This means that for common diseases, such as AMD, many environmental and genetic factors combine in a patient to give rise to the disease, putting the patient at increased risk. Conversely, in rare Mendelian genetic diseases, the genotype at a specific locus is more powerful than those in common diseases, and can be safely said to “cause” the disease, Dr. Stone said.

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An example of the latter was found in a recent study of North Carolina macular dystrophy that reported identification of the gene responsible for the disease. Researchers found that a single nucleotide variance, 14,000 base pairs upstream from PRDM13, could interrupt normal development of the macula and cause North Carolina macular dystrophy (Small et al. Ophthalmology. 2016;123:9-18; DOI:

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A person born with this variant is more than 10,000 times likely to develop the disease than a random person of the same age in the general population, Dr. Stone said.

This is in contrast to a high-risk person with gene CFH/ARMS2, who is perhaps 5 to 10 times more likely to develop AMD compared with an age-matched person in the general population.

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Though genetic testing is useful in Mendelian diseases, clinicians accurately can predict the risk of visual loss from AMD, and genetic testing should not be used routinely to determine that risk, he emphasized.

Transplantable retinal cells from skin?


In another area, a research discovery by a Japanese group in 2007 also may translate into a promising AMD therapy.

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Investigators “discovered that by transiently expressing four cancer genes in adult cells, such as keratinocytes, the differentiated state can be erased and the cells turned into cells similar to those present in an embryo shortly after conception,” Dr. Stone recounted. “The discovery of these iPSCs raises the possibility of making transplantable retinal cells from a patient’s own skin and avoiding the lifelong immunosuppression often required when transplanting unmatched tissues.”

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Researchers in his laboratory in Iowa City have expanded on this work and ultimately produced retinal pigment epithelium and photoreceptor precursors from the iPSCs.

“By using some version of this research,” Dr. Stone said, “scientists will eventually be able to rebuild the human macula and restore some useful central vision in patients with extensive geographic atrophy.”

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Edwin Stone, MD, PhD


This article was adapted from Dr. Stone’s presentation at Retina Subspecialty Day during the 2015 meeting of the American Academy of Ophthalmology. Dr. Stone has no relevant financial interests to disclose.


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