Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model

• Published in: Journal of ocular pharmacology and therapeutics Vol. 28; no. 2; p. 194
• Main Authors: Hosseini, Alireza, Lattanzio, Jr, Frank A, Samudre, Sandeep S, DiSandro, Giovanni, Sheppard, Jr, John D, Williams, Patricia B
• Format: Journal Article
• Language: English
• Published: United States 01.04.2012
• Subjects: Administration, Topical; Animals; Chromatography, High Pressure Liquid; Cornea - drug effects; Corneal Transplantation; Dose-Response Relationship, Drug; Drug Stability; Female; Graft Rejection - prevention & control; Graft Survival - drug effects; Humans; In Vitro Techniques; Morpholinos - administration & dosage; Morpholinos - adverse effects; Morpholinos - therapeutic use; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - adverse effects; Oligonucleotides, Antisense - therapeutic use; Rabbits; Rats; Rats, Inbred Lew; Treatment Outcome
• ISSN: 1557-7732
• DOI: 10.1089/jop.2011.0135

The cornea is one of the most commonly transplanted tissues. The morpholino-oligomer antisense compound AVI-5126 suppresses expression of proto-oncogene c-myc, a key factor in transplant rejection. AVI-5126 was evaluated in a rat cornea transplant model. Donor corneas obtained from August x Copenhagen Irish rats were stored in Optisol™ containing 1.0 or 0.5 mg/mL AVI-5126 or Optisol alone for 24 h before transplant. Recipient Lewis rats were treated topically 3x/d with TobraDex™ and with 1.0 or 0.5 mg/mL of AVI-5126 or saline with daily monitoring for rejection using a modified McDonald-Shadduck Slit Lamp Scale. Using the high-performance liquid chromatography technique, the stability of AVI-5126 (0.5 mg/mL) in Optisol was evaluated for 30 days. AVI-5126 corneal transport was measured using Ussing chamber mounted rabbit corneas. The potential ocular toxicity of AVI-5126 (0.5 mg/mL) was evaluated after 8 days of 3x/d topical application in rats and in-vitro by incubation of human corneas for 8 days. Cornea storage in Optisol containing 1.0 mg/mL AVI-5126 plus post-transplant topical tid AVI-5126 (1.0 mg/mL) application significantly increased graft survival (7.0±1.6 days) versus 5.0±0.8 days for Optisol alone storage plus post-transplant topical tid saline application (P<0.001). After 30 days of storage, no significant degradation of AVI-5126 in Optisol was noted by high-performance liquid chromatography analysis. After 24 h, 5 μg/mL (1% of total dose) crossed the corneas mounted in Ussing chambers. Neither extended topical application of AVI-5126 to rats nor incubation of human corneas in AVI-5126 decreased endothelial cell density. Graft rejection was significantly delayed after pretransplantation storage of graft corneas in Optisol containing AVI-5126 followed by topical application of AVI-5126 post-transplantation. AVI-5126 was well tolerated, stable, and effectively penetrated the cornea.