Introducing Gustavo D. Aguirre, the 2017 Recipient of the Proctor Medal.

Major advances in vision research and clinical ophthalmology have occurred because of seminal findings by individual investigators, usually though only after years of persistent, hard work. I believe this to be the case with the work of Dr. Gustavo Aguirre in developing, characterizing, and subsequently using his unique animal models of inherited retinal degeneration (RD) in preclinical safety and efficacy trials. These models have been the basis of most of the current clinical trials for inherited RD diseases and, more broadly, many treatments for other tissues of the eye and body. Because of this long-term, groundbreaking body of work, he now fully deserves recognition through the Proctor Award (Fig. 1). Dr. Aguirre has a long history of discovering and characterizing large-animal models of RD and developing the most appropriate ones for translational studies. This has proceeded over the past 3 decades, such that, by my count, he has given us at least 17 important models that can be used to study gene mutations, cellular protein changes in photoreceptor cell degeneration and death, and also in establishing preclinical criteria for subsequent clinical trials. Of course, this is just what the Food and Drug Administration (FDA) wants as a prelude to a clinical trial. He has done this not only in his own laboratory, but by his skill in forging productive relationships with a long list of distinguished collaborators. Figure 2 shows Gus with some of his principal collaborators, William Beltran on the left, Art Cideciyan next to Gus, and then Samuel Jacobson. The only one missing is Bill Hauswirth, master of the gene vector. In fact, his work on canine inherited RDs began back in the mid-1970s, with seminal publications on a progressive retinal atrophy in Irish setter dogs that he called rod-cone dysplasia (rcd1) in which the underlying problem in this early-onset RD was found to be in the cyclic GMP phosphodiesterase gene, just as in the rd1 mouse and later human patients. All this work, and then throughout the 1980s and early 1990s, was accompanied by a meticulous description of cellular changes in the degenerative process in the animal models and similarities to human RD disease pathophysiology that later would be crucial in establishing the dog diseases as authentic therapy models for the human. At about this time, Dr. Aguirre established his credentials in the gene therapy arena by first showing that retroviral-mediated transfer of normal b-glucuronidase cDNA to mutant RPE cells in culture completely reversed the disease and, with colleagues at Penn and other institutions, showed that the ocular disease phenotype in MPSI and MPSVII animal models was corrected by either systemic gene therapy or bone marrow transplantation. All this groundwork led to the spectacular finding that gene therapy could, in fact, restore vision in a canine model of childhood blindness: the RPE65 mutation. I believe that this publication forms the basis for most of the subsequent gene therapy studies we now have in the human on the RPE65 mutation and many other diseases as well. In the mid-1990s, Dr. Aguirre began to establish the genetic underpinnings of the canine models, for example, the X-linked nature of what we now know as XLPRA. He established molecular diagnostic tests for the rcd1 dysplasia, and the cloning and characterization of the cDNA as well as the locus homology between canine prcd and RP17 in the human. He also mapped and described the pathology of canine X-linked progressive retinal atrophy, pinpointing the locus homolog of human RP3. As with the gene therapy breakthrough using the RPE65 dog model, 2002 saw the publication of another groundbreaking study by Dr. Aguirre and his collaborators, that is, establishing that delivery of the neurotrophic agent CNTF using encapsulated cell technology reduces photoreceptor degeneration in the rcd1 model of RD. This work clearly established preclinical proof of concept for safety and efficacy, a necessary prelude to current human clinical trials on both RP and AMD. Many more advances came in the decade between 2000 and 2010, cementing in, for example, the safety of ocular gene therapy using AAV2 vectors and validating their use for human trials of Leber congenital amaurosis (LCA), as well as giving a further green light in proceeding with human therapy trials by demonstrating the intactness and responses of canine and human visual cortices in early retinal blindness caused by RPE65 gene mutations. Building on decades of this basic work, there has been an explosion in further movement to clinical trials and ultimate