title: Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: T.R. Lee Center for Ocular Pharmacology, Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA. hosseia@evms.edu
authors.forename: Alireza
authors.initials: A
authors.lastname: Hosseini
authors.forename: Frank A
authors.initials: FA
authors.lastname: Lattanzio
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Samudre
authors.forename: Giovanni
authors.initials: G
authors.lastname: DiSandro
authors.forename: John D
authors.initials: JD
authors.lastname: Sheppard
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Williams
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000187:drug effects; D016039:Corneal Transplantation; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D060172:Morpholinos / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome
chemical_list: C574128:AVI-5126; C000715470:MAS1 protein, human; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas