449 CURRENT RESEARCH SURVEY OF OPHTHALMOLOGY VOLUME 47 • NUMBER 5 • SEPTEMBER–OCTOBER 2002 © 2002 by Elsevier Science Inc. 0039-6257/02/$–see front matter All rights reserved. PII S0039-6257(02)00336-3 EDWARD COTLIER AND ROBERT WEINREB, EDITORS Gene Therapy for Genetic and Acquired Retinal Diseases Edward Chaum, MD, PhD, 1 and Mark P. Hatton, MD 2 1 Departments of Ophthalmology, Pediatrics, Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee; and 2 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachussetts, USA Abstract. We present an overview of the current status of basic science and translational research being applied to gene therapy for eye disease, focusing on diseases of the retina. We discuss the viral and nonviral methods being used to transfer genes to the retina and retinal pigment epithelium, and the advantages and disadvantages of each approach. We review the various genetic and somatic treat- ment strategies that are being used for genetically determined and acquired diseases of the retina, including gene replacement, gene silencing by ribozymes and antisense oligonucleotides, suicide gene therapy, antiapoptosis, and growth factor therapies. The rationales for the specific therapeutic approaches to each disease are discussed. Schematics of gene transfer methods and therapeutic approaches are presented together with a glossary of gene transfer terminology. ( Surv Ophthalmol 47: 449–469, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. apoptosis • gene therapy • growth factors • proliferative vitreoretinopathy • retinal pigment epithelium • retina • retinal degeneration • retinitis pigmentosa • retinoblastoma • ribozymes • transfection • viruses Over the past decade there has been an explosion of research that uses gene transfer techniques to probe the molecular mechanisms directing retinal differenti- ation and development and applies gene therapy to the treatment of ocular diseases. The delivery of for- eign genes to ocular tissues to modify the genotype and phenotype of cells is enabling novel approaches to the understanding and treatment of many eye diseases. We review current gene transfer methods and the strategies with which these are being applied to gene therapy of eye disease, with particular emphasis on diseases of the retina. Because of the availability of genetically well-defined and -characterized animal models and the ease of gene delivery to the retina and vitreous, most research in ocular gene therapy has been directed at the treatment of retinal degen- erative diseases. The literature demonstrates well the varied approaches to gene delivery in the eye and the strategies being employed to correct the geneti- cally disparate molecular defects that lead to retinal degeneration and to modify abnormal cellular phe- notypes to ameliorate disease progression. The ideal gene transfer method would transfect genes to a specific cell type with high efficiency; deliver a re- placement gene with a regulatory sequence to the nu- cleus, where it would become integrated into the host genome in a non-mutagenic fashion and be expressed or regulated; transduce cells efficiently, independent of