Lloyd Paul Aiello, M.D., Ph.D.
Dr. Lloyd Paul Aiello is Professor of Ophthalmology at Harvard Medical School, Director of Joslin’s Beetham Eye Institute, co-head of Joslin's Section of Vascular Cell Biology, Vice President of Ophthalmology at Joslin, Vice Chair for Centers of Excellence at Harvard Department of Ophthalmology, and Founding Chair of the National Eye Institute Diabetic Retinopathy Clinical Research Network. He received his doctoral degree in biochemistry and a medical degree from Boston University School of Medicine. He completed residency in ophthalmology at the Wilmer Ophthalmological Institute at Johns Hopkins University and Hospital before coming to the Joslin Diabetes Center, where he completed both a clinical vitreoretinal, and a research fellowship. He joined the Joslin staff in 1994.
A third-generation Joslin ophthalmologist, Dr. Aiello is committed to eliminating visual loss resulting from diabetic retinopathy (a condition in which abnormal blood vessels grow on the retina) and other related retinopathies which account for the majority of blindness among working-age individuals in America and other developed countries. These conditions are usually caused by insufficient blood perfusion with subsequent proliferation of sight-damaging blood vessels and abnormal vessel leakage in the retina. Dr. Aiello’s research aims to determine the biochemistry and molecular mechanisms underlying early diabetic retinopathy and other retinal vascular disorders, and then develop and test novel therapeutic interventions through rigorous translational and clinical trial research.
As of November 2009, Dr Aiello is the author of 116 original papers and 193 publications including contributions to the New England Journal of Medicine, Nature Medicine, PNAS, Journal of Biological Chemistry, Journal of Clinical Investigation, Diabetes, Lancet and many others covering a wide range of topics in diabetic eye disease. Dr Aiello is the recipient of more than 35 national and international awards and honors. These awards include the Alcon Research Institute Award, ARVO/Pfizer Ophthalmics Translational Research Award, Award of Merit in Retina Research from the Retina Society, Senior Achievement Award from the American Academy of Ophthalmology, Dolly Green Scholar Award and the Special Research Scholar Award from the Research to Prevent Blindness Foundation, Rosenthal Foundation Award from the Macula Society, Charles Schepens Award in Research, Outstanding Foreign Investigator Award from the Japan Society of Diabetic Complications in Kyoto, the ARVO Fellow Silver Medal and the Novartis Award in Diabetes. He has served as Chair for the Lions Club International SightFirst Diabetic Retinopathy Research Program Review Panel, the Complications Section of the Juvenile Diabetes Research Foundation (JDRF) Medical Science Review Committee and the Clinical Investigation Section of the JDRF.
Dr. Aiello and several Joslin scientists—including George L. King, M.D., Head of the Section on Vascular Cell Biology—published the first evidence that protein kinase C-beta (PKC-beta) is involved in excessive blood-vessel growth and diabetic retinopathy. The discovery led the scientists to develop a PKC-beta inhibitor that interrupts the actions of this protein.
Dr. Aiello, recognized internationally for his leadership in diabetic retinopathy, has been chairman of three multi-center, multi-national, phase 3 clinical trials using this PKC-beta inhibitor. The results will determine whether the inhibitor, which is given orally, can delay or prevent development of the sight-threatening conditions of proliferative diabetic retinopathy or diabetic macular edema (swelling of the retinal tissue caused by leaking blood vessels). Results from these studies thus far have supported an application to the Food and Drug Administration, which has deemed the drug “Approvable” for this indication pending additional study data.
In related research, Dr. Aiello’s laboratory made significant progress toward understanding and manipulating the expression, regulation and signaling functions of vascular endothelial growth factor (VEGF) and its receptors. Several years ago, Drs. King and Aiello reported that VEGF, a major growth factor for blood vessels, is elevated in the eye fluids of patients with diabetes who have proliferative diabetic retinopathy. Dr Aiello has been a leader in ongoing pivotal trials that will determine the benefit of potent VEGF inhibitors for the treatment of diabetic macular edema.
Dr. Aiello’s research has focused extensively on understanding the mechanisms of VEGF expression. For instance, his laboratory found that there are signaling mechanisms for this growth factor in retinal cells, and that factors influencing the expression of VEGF include hypoxia (lack of oxygen), high glucose, diabetes and basic fibroblast growth factor (bFGF), a mediating growth factor. Dr. Aiello also determined that increased levels of VEGF are normalized when proliferative retinopathy is in remission, as observed following vitrectomy (surgical replacement of the gel-like substance in the eye with clear fluid) or panretinal laser photocoagulation of the retina - a treatment pioneered at Joslin by W.P. Beetham, M.D., and Lloyd M. Aiello, M.D., the Founding Director of the Beetham Eye Institute and Dr. Lloyd Paul Aiello’s grandfather and father, respectively. Dr. Aiello’s laboratory has also uncovered portions of the molecular mechanisms by which hypertension exacerbates diabetic retinopathy and has evaluated the effects of diabetes on retinal blood flow with colleagues Allen Clermont and Sven-Erik Bursell, Ph.D.
In addition, Dr Aiello has spearheaded rigorous clinical trial research in diabetic eye disease that have evaluated and helped define the role of PKC beta inhibitors, intraocular steroids, laser photocoagulation techniques, vitamins, ocular coherence tomography, autorefraction, PPAR gamma agonists and VEGF inhibitors.
Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris FL, Glassman AR, Ip MS, Miller KM, for the Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2009; in press.
Geraldes P, Yamamoto-Hiraoka J, Matsumoto M, Clermont A, Leigtes M, Marette A, Aiello LP, Kern TS, King GL. Activation of PKCδ and SHP1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med. 2009; in press.
Diabetic Retinopathy Clinical Research Network. Three-year Follow Up of a Randomized Trial Comparing Focal/Grid Photocoagulation and Intravitreal Triamcinolone for Diabetic Macular Edema. Arch Ophthalmol. 2009 Mar;127(3):245-251.
Progression of Diabetic Retinopathy at 1 Year and 2 Years in a Retrospective Analysis of a Randomized Clinical Trial Comparing Intravitreal Triamcinolone with Focal/Grid Photocoagulation. Arch. Ophthalmol. 2009, in press.
Shen LQ, Child A, Weber GM, Folkman J, Aiello LP. Rosiglitazone May Delay Onset of Proliferative Diabetic Retinopathy. Arch. Ophthalmol. 2008;126(6):793-9.
Tong Z, Yang Z, Patel S, Chen H, Gibbs D, Zeng J, Yang X, Ma X, Harmon J, Pearson E, Beuhler J, Luo L, Hau VS, Kaminoh Y, Zabriskie NA, Sun JK, Prakash M, Haman R, Tonna S, Constantine R, Ronquillo CC, Sadda SV, Avery RL, Brand JM, London N, King GL, Bernstein PS, Watkins S, Genetics of Diabetes and Diabetic Complication Study Group, Jorde LB, Li DY, Aiello LP, Pollak MR, Zhang K. Promoter polymorphism of the Erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci, 2008;105:6998-7003.
The Diabetic Retinopathy Clinical Research Network. Manuscript Writing Committee: Ip MS, Edwards AR, Beck RW, Bressler NM, Aiello LP, Browning DJ, Elman MJ, Friedman SM, Ferris FL, Glassman AG, Kollman C, Price A. A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Focal/Grid Photocoagulation for Diabetic Macular Edema. Ophthalmology. 2008;115(9):1447-9.
The PKC-DMES Study Group. Manuscript Writing & Study Executive Committee: Aiello LP (Chair); Davis MD, Milton RC, Sheetz MJ. Effect of Ruboxistaurin, a PKC Isoform-Selective Inhibitor, in Patients with Diabetic Macular Edema: 30-month Results of the Randomized PKC-DMES Clinical Trial. Arch Ophthalmol. 2007;125:318-324.
The Diabetic Retinopathy Clinical Research Network. Manuscript Writing Committee: Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, Bressler NM, Danis RP, Kinyoun JL, Nguyen QD, Bhavasar AR, Gottlieb J, Pieramici DJ, Rauser ME, Apte RS, and Lim JI. Relationship Between Optical Coherence Tomography-measured Central Retinal Thickness and Visual Acuity in Diabetic Macular Edema. Ophthalmol. 2007;114:(3):525-36.
The Diabetic Retinopathy Clinical Research Network. Manuscript Writing Committee: Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP, Davis MD, Feman SS, Ferris FL, Friedman SM, Garcia CA, Glassman AR, Han DP, Le D, Kollman C, Lauer AK, Recchia FM, Solomon SD. Comparison of Modified-Early Treatment Diabetic Retinopathy Study and Mild Macular Grid Laser Photocoagulation Strategies for Diabetic Macular Edema. Arch. Ophthalmol. 2007;125(4):469-480.
Gao B, Clermont A, Rook S, Fonda SJ, Srinivasan V, Wojtkowski MD, Fujimoto JG, Avery RL, Arrigg PG, Bursell SE, Aiello LP, Feener EP. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat. Med. 2007;13(2):181-188.
Keenan HA, Costacou T, Sun JK, Doria A, Cavallerano JD, Coney J, Orchard TJ, Aiello LP, King GL. Clinical Factors Associated with Resistance to Microvascular Complications in Diabetic Patients of Extreme Disease Duration: The Fifty-Year Medalist Study. Diabetes Care. 2007;30(8):1995-1997.
The Diabetic Retinopathy Clinical Research Network. Manuscript Writing Committee: Chew E, Strauber S, Beck R, Aiello LP, Antoszyk A, Bressler N, Browning D, Danis R, Fan J, Flaxel C, Friedman S, Glassman A, Kollman C, Lazarus H. Randomized Trial of Peribulbar Triamcinolone Acetonide with and without Focal Photocoagulation for Mild Diabetic Macular Edema. Ophthalmol. 2007:114(6):1190-1196.
Geraldes P, Yamagata M, Rook S, Sassa Y, Ma RC, Clermont A, Aiello LP, Feener E, King GL. Glypican 4, a membrane binding protein for bactericidal/permeability-increasing protein signaling pathways in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 2007;Dec;48(12):5750-5.
The Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007 Oct;114(10):1860-7.
The PKC-DRS2 Study Group. Manuscript Writing & Study Executive Committee: Aiello LP (Chair), Davis MD, Milton RC, Sheetz MJ, Vignati L, Zhi X. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology [on line] September 19, 2006.
The PKC-DMES Study Group. Manuscript Writing & Study Executive Committee: Aiello LP (Chair), Davis MD, Milton RC, Sheetz MJ. Effect of ruboxistaurin, a PKC b isoform-selective inhibitor, in patients with diabetic macular edema: 30-month results of the randomized PKC-DMES clinical trial. Ophthalmology 2006,
Clermont AC, Cahill M, Salti H, Rook SL, Rask-Madsen C, Goddard L, Wong JS, Bursell D, Bursell SE, Aiello LP. Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics. Invest Ophthalmol Vis Sci 47:2701-2708, 2006.
Aiello LP, Clermont A, Arora V, Davis MD, Sheetz MJ, Bursell SE. Inhibition of PKC b# by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Invest Ophthalmol Vis Sci 47:86-92, 2006.
The PKC-DRS Study Group. Manuscript Writing & Study Executive Committee: Aiello LP (Chair), Davis MD, Milton RC, Sheetz MJ, Arora V, Vignati L. The Effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C b Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54:2188-2197, 2005.
Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LEH. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 92:10457-10461,1995.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480-1487, 1994.