Dr. Dunaief in his lab.
By Rebecca Salowe
Scheie Vision Summer 2016
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly in the United States. This condition damages the macula, the sensitive region of the retina that provides sharp central vision. Despite its high prevalence, the pathogenesis of AMD remains poorly understood.
Josh Dunaief, MD, PhD, the Adele Niessen Professor of Ophthalmology, believes that iron overload may contribute to this debilitating condition.
Dr. Dunaief received his MD/PhD at Columbia University, where he first began conducting research on aging. He was surprised to learn how many elderly individuals were affected by AMD and had few effective treatment options. He began to research oxidative stress, which occurs when free radicals (such as iron) damage proteins, lipids, and DNA.
“My lab members found that AMD retinas have significantly more iron than age-matched controls without the disease,” said Dr. Dunaief. “Excess iron is a major source of oxidative stress.”
Additionally, patients with certain forms of hereditary iron overload can develop AMD at an early age. High levels of iron intake through red meat or excessive iron supplementation seem to increase the risk of AMD as well.
Dr. Dunaief hypothesizes that cells affected by AMD may respond to inflammation by holding onto iron, as they would in the case of a true infection. However, unlike the healthy iron bound to proteins throughout the body, this “free” iron can accumulate and damage cells.
A drug that targets and binds excess iron may help to slow or halt the progression of AMD. There is one FDA-approved drug on the market with this function, but it has serious limitations for AMD patients.
“One percent of patients who take this drug have a decrease in their white blood cells,” said Dr. Dunaief. “Thus, patients on this drug must have their white blood cell number checked each week. This is unrealistic to ask of AMD patients who have had their disease for decades.”
To address the need for a safer drug, Dr. Dunaief and Dr. Benjamin Kim, Assistant Professor of Ophthalmology, launched a clinical trial testing the efficacy of lipoic acid, an anti-oxidant and iron-binding drug. This drug will be administered to patients with geographic atrophy (an advanced form of dry AMD) for 18 months. AMD progression will be compared between treated patients and a control group taking a placebo.
Iron overload may also result from alterations in proteins involved in iron import and export from the retina. For example, Dr. Dunaief recently showed that a mutation in ferroportin, an iron transporter protein, leads to increased iron levels in the retina and retinal degeneration. This research was featured on the cover of FASEB Journal.
“Normally, ferroportin carries excess iron out of cells,” explained Dr. Dunaief. “However, cells affected by AMD do not upregulate this protein, so they cannot get rid of excess iron.”
A treatment approach that increases ferroportin levels in the retina could be very valuable for these patients. In the future, a library of candidate compounds could be screened to identify a drug candidate that increases ferroportin levels. In addition, gene therapy could be explored to overexpress this protein in the retina. This approach is currently being tested in mice with retinal iron overload in collaboration with the Center for Advanced Retinal and Ocular Therapeutics (CAROT).
Research on countering iron overload may have far-reaching consequences for AMD patients. Limiting damage from iron will not bring dead photoreceptors back to life, but it may slow or halt the progression of AMD and other debilitating eye diseases.