Dr. Claudio Punzo receives BrightFocus Grant

Elucidating how smoking contributes to AMD.

Age-related macular degeneration (AMD) is a leading cause for blindness. Among the non-genetic risk factors smoking confers the highest risk for progression to the advanced stages of geographic atrophy (GA) and exudative AMD. However, how smoking contributes to AMD remains elusive. Many smokers develop emphysema, which is a lung condition that causes shortness of breath due to an extracellular matrix breakdown of the alveoli.

In smokers, this breakdown is driven in part by a protease/antiprotease imbalance, specifically the inactivation of the serum antiprotease alpha-1 antitrypsin (AAT) by the free radicals contained in smoke. One of its roles of AAT is to inhibit extracellular elastase and collagenase activity. Because the elastin and collagen rich Bruch’s membrane (BM) and choroid are the primary structures affected in AMD, the same protease/antiprotease imbalance that causes emphysema could also contribute to advanced AMD in smokers.

To test if serum AAT level are linked to AMD, we analyzed the eyes of aged AAT knockout (KO) mice. We found that AAT-KO mice develop large geographic atrophy lesions with age. The grant will further explore the link between serum AAT levels, smoking and the risk for advanced AMD.

Below is a picture of a mouse with this mutation (AAT knockout) and central geographic atrophy at 18 months of age.