Gustavo D. Aguirre
Professor of Medical Genetics and OphthalmologyContact Information
3900 Delancey St.
Philadelphia, PA 19104
Bachelor University of Pennsylvania, 1964
VMD (Veterinary Medicine) University of Pennsylvania, 1968
PhD University of Pennsylvania, 1975
Description of Research Expertise
• Molecular bases of inherited blindness
Key words: Retinal degeneration, photoreceptor cells, gene therapy.
Description of Research
Our research is directed to identifying the genetic causes of inherited blindness, identifying the mechanisms linking mutation to disease, and developing treatment approaches. Studies are done in the dog model which is affected a large variety of inherited photoreceptor diseases that are now being characterized at the molecular level. For "disease hunting" work, we have used two general approaches. The first, phenotype directed candidate gene analysis, directs selection of a small subset of candidate genes that, when mutated, would be expected to result in the observed phenotype. The second approach utilizes informative pedigree resources we have developed to carry out genome wide scans to identify the disease bearing chromosomal region. Subsequently, positional cloning of the gene and identification of the causative mutation is carried out. Once the genes and mutations are identified, we use molecular and proteomic approaches to examine the disease mechanism. In parallel, gene based therapies are developed with the goal of restoring function and preventing the degeneration of the mutant photoreceptor cells.
Examples of specific projects include:??• RPGR: mechanisms of disease and treatment. The RP3 form of X-linked retinitis pigmentosa (XLRP) is caused by mutations in the RP GTPase regulator (RPGR) gene. This is a uniformly severe, early onset retinal disease in man, and mutations in RPGR account for the majority of XLRP, and for ~8-25% of all molecularly diagnosed RP cases. Besides man, the dog is the only other species in which naturally occurring mutations in RPGRORF15 occur. Two different ORF15 microdeletions have been identified that are termed XLPRA1 and XLPRA2 because they are different forms of X linked progressive retinal atrophy, the dog counterpart of human RP. To examine the mechanism of disease, our lab is using microarray analysis to characterize global gene expression profiles, and determine the gene classes that are activated or suppressed at different stages of the disease. In parallel, proteomic analysis examine the different RPGR protein isoforms, and their distribution in retina and other tissues. Therapy studies are starting and will use AAV2/5 vectors carrying a truncated but functional gene, and regulated by promoters that target expression to rods and/or cones.??• Rhodopsin and light damage. Mutations in the rhodopsin gene are one of the most common causes of autosomal dominant retinits pigmentosa. Dogs have a mutation in this gene that substitutes arginine for threonine at the first consensus glycosylation site. This renders the mutant rhodopsin exquisitively sensitive to light levels that are within the normal intensity range. Following light exposures, the photoreceptors die and retina degenerates within a brief time period. Using a standard light exposure paradigm, we are examining the signaling pathways that become activated following light exposure to identify those involved in cell survival and cell death.??• Bestrophin mutations and disease. Mutations in the Bestrophin gene impair the function of calcium dependent chloride channels in the retinal pigment epithelium (RPE), and cause Best Macular Dystrophy (BMD), a disease of young children and young adults that results in central visual impairment. We have identified 2 different mutations in the Bestrophin gene in dogs that cause a disease similar to BMD although with multifocal distribution. We now aim to use a combination of cell culture, molecular and proteomic approaches to characterize normal and mutant Bestrophin expression, distribution and function in the RPE as an initial approach to examine the functional consequences of these mutations.
Kukekova, A.V., Goldstein, O., Johnson, J.L., Richardson, M.A., Pearce-Kelling, S.E., Swaroop, A., Friedman, J.S., Aguirre, G.D., Acland, G.M.: Canine RD3 mutation establishes rod cone dysplasia type 2 (rcd2) as the canine ortholog of human and murine rd3. Mammalian Genome (published on-line) 2009.
Komáromy, A.M., Acland, G.M and Aguirre, G.D.: Operating in the dark: a night vision system for surgery in retinas susceptible to light damage. Arch. of Ophthalmology Page: 714-717, 2008.
Komáromy, A.M., Alexander, J.J., Cooper, A.E., Chiodo, V.A., Acland, G.M., Hauswirth, W.W. and Aguirre, G.D.: Targeting gene expression to cones with human cone opsin promoters in recombinant AAV Gene Therapy 15: 1049-1055, 2008.
Beltran, William A. Wen, Rong. Acland, Gregory M. Aguirre, Gustavo D.: Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina. Experimental Eye Research 84(4): 753-71, Apr 2007.
Guziewicz, Karina E. Zangerl, Barbara. Lindauer, Sarah J. Mullins, Robert F. Sandmeyer, Lynne S. Grahn, Bruce H. Stone, Edwin M. Acland, Gregory M. Aguirre, Gustavo D.: Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Investigative Ophthalmology & Visual Science 48(5): 1959-67, May 2007.
Gu, D., Beltran, W.A., Li, Z., Acland, G.M. and Aguirre, G.D. : Clinical light exposure, photoreceptor degeneration and AP-1 activation: a cell death or cell survival signal in the rhodopsin mutant retina? Inv. Ophthalm. Vis. Sci. 2007.
Aguirre, G.K., Komaromy, A.M., Cideciyan, A.V., Brainard, D.H., Alemán, T.S., Roman, A.J., Avants, B.B., Gee, J.C., Korczykowski, M., Hauswirth, W.W., Acland, G.M., Aguirre, G.D., and Jacobson, S.G: Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation PLoS Med 4: 1117-1127, 2007.
Beltran, W.A., Wen, R., Acland, G.M. and Aguirre, G.D: Ciliary neurotrophic factor (CNTF) fails to rescue photoreceptors and causes peripheral remodeling in RPGR mutant retina Exp. Eye Research 84: 753-771, 2007.
Zangerl, Barbara. Goldstein, Orly. Philp, Alisdair R. Lindauer, Sarah J P. Pearce-Kelling, Susan E. Mullins, Robert F. Graphodatsky, Alexander S. Ripoll, Daniel. Felix, Jeanette S. Stone, Edwin M. Acland, Gregory M. Aguirre, Gustavo D.: Identical mutation in a novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa in humans. Genomics 88(5): 551-63, Nov 2006.