Baculoviral IAP Repeat-Containing-4 Protects Optic Nerve Axons in a Rat Glaucoma Model

• Published in: Molecular therapy Vol. 5; no. 6; pp. 780 - 787
• Main Authors: McKinnon, Stuart J., Lehman, Donna M., Tahzib, N.Grace, Ransom, Nancy L., Reitsamer, Herbert A., Liston, Peter, LaCasse, Eric, Li, Qiuhong, Korneluk, Robert G., Hauswirth, William W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2002; Elsevier Limited
• Subjects: adeno-associated virus; animal; Animals; Apoptosis; Axons - pathology; Caspase Inhibitors; caspases; Cell Survival; Dependovirus - genetics; Disease Models, Animal; Gene expression; Gene therapy; Genetic Therapy; Genetic Vectors; Glaucoma; Glaucoma - metabolism; Glaucoma - pathology; Glaucoma - prevention & control; Humans; Hypertension; Intraocular Pressure; ocular hypertension; Ophthalmology; Optic nerve; Optic Nerve - pathology; Photoreceptors; Proteins; Proteins - genetics; Proteins - therapeutic use; Rats; Retina; retinal ganglion cells; Retinal Ganglion Cells - metabolism; Transgenes; Vectors (Biology); X-linked IAP; X-Linked Inhibitor of Apoptosis Protein; Canada; United States > US; Ottawa Ontario Canada; models; X-linked IAP; ocular hypertension; intraocular pressure; glaucoma; apoptosis; gene therapy; animal; adeno-associated virus; retinal ganglion cells; rats; caspases
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1006/mthe.2002.0608

Gene therapy represents an attractive approach for the treatment of eye diseases such as glaucoma. Ocular administration of viral vectors produces localized retinal gene expression with reduced risks of side effects reported with systemic administration of viral vectors. Recombinant adeno-associated viral (AAV) vectors have proven effective in producing long-term retinal gene expression, due to stable integration of DNA into the genome and lack of host immune response to the virus. Recently developed AAV constructs using the chicken β-actin (CBA) promoter drive highly efficient transgene expression in retinal ganglion cells (RGCs), photoreceptors, and pigment epithelium. Rats were given unilateral intravitreal injections of AAV-CBA vector coding for human baculoviral IAP repeat-containing protein-4 (BIRC4), a potent caspase inhibitor. Ocular hypertension was induced in the same eye by sclerosis of aqueous humor outflow channels. After chronic exposure to elevated intraocular pressure, we performed optic nerve axon counts to determine the neuroprotective effects of retinal BIRC4 expression, and compared axon survival with vector and balanced salt solution control groups. Gene therapy delivering BIRC4 significantly promoted optic nerve axon survival in a chronic ocular hypertensive model of rat glaucoma. Blocking RGC apoptosis with caspase inhibitors represents a promising approach for treatment of human glaucoma.