May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Topical Phosphorodiamidate Morpholino Oligomer Antisense Compounds Effectivly Delay Cornea Rejection in a Transplant Rat Model
Author Affiliations & Notes
  • J. T. Doss, Jr.
    Eastern Virginia Medical School, Norfolk, Virginia
    Ophthalmology,
  • A. Hosseini
    Eastern Virginia Medical School, Norfolk, Virginia
    T.R. Lee Center for Ocular Pharmacology, Physiological Sciences,
  • F. A. Lattanzio, Jr.
    Eastern Virginia Medical School, Norfolk, Virginia
    T.R. Lee Center for Ocular Pharmacology, Physiological Sciences,
  • S. S. Samudre
    Eastern Virginia Medical School, Norfolk, Virginia
    T.R. Lee Center for Ocular Pharmacology, Physiological Sciences,
  • J. Davis
    Eastern Virginia Medical School, Norfolk, Virginia
    Ophthalmology,
  • J. D. Sheppard, Jr.
    Eastern Virginia Medical School, Norfolk, Virginia
    EyeRx Research,
  • P. B. Williams
    Eastern Virginia Medical School, Norfolk, Virginia
    EyeRx Research,
  • P. Iverson
    AVI BioPharma Inc., Corvallis, Oregon
  • P. O'Hanley
    AVI BioPharma Inc., Corvallis, Oregon
  • Footnotes
    Commercial Relationships  J.T. Doss, None; A. Hosseini, None; F.A. Lattanzio, None; S.S. Samudre, None; J. Davis, None; J.D. Sheppard, None; P.B. Williams, None; P. Iverson, AVI BioPharma Inc., E; P. O'Hanley, AVI BioPharma Inc., E.
  • Footnotes
    Support  AVI BioPharma Inc.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5764. doi:https://doi.org/
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      J. T. Doss, Jr., A. Hosseini, F. A. Lattanzio, Jr., S. S. Samudre, J. Davis, J. D. Sheppard, Jr., P. B. Williams, P. Iverson, P. O'Hanley; Topical Phosphorodiamidate Morpholino Oligomer Antisense Compounds Effectivly Delay Cornea Rejection in a Transplant Rat Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5764. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Corneas are the most common and successfully transplanted tissue. However, if rejection occurs, the probability of a subsequent successful transplantation declines precipitously. Phosphorodiamidate morpholino oligomer (PMO) antisense compounds, AVI-4126 and AVI-5126, suppress c-myc expression. Stability and tolerability of AVI-4126 and AVI-5126 were previously examined in rat and rabbit models. To evaluate their ability to inhibit corneal rejection, we compared incubation of corneas stored in OptisolTM + AVI-4126 or AVI-5126 with or without post transplant topical treatment with AVI-4126 or AVI-5126.

Methods: : In vivo sterile cornea transplants were performing by transplanting donor corneas from ACI rats to right eye of Lewis rats using 3mm trephine and 10-0 nylon suture. In a masked, randomized fashion, corneas from ACI rats were preserved in either 0.5 or 1mg/ml AVI-4126 or AVI-5126 in OptisolTM or in OptisolTM alone for 24 hr before transplantion. All rats were treated post-operatively with topical TobradexTM TID until rejection occurred. Some Lewis rats received TID post transplant topical treatment with 0.5 or 1mg/ml AVI-5126 or with the vehicle, 0.9% NaCl, as a control. There was daily toxicity monitioring using a modified McDonald-Shadduck System: Slit Lamp Scale for Ocular Irritation. Rejection criteria were an opacity score > 2 or a total score > 4.5.

Results: : Transplanted rats with graft corneas stored in either 0.5 or 1mg/ml AVI-5126 with post transplant TID 1mg/ml AVI-5126 showed significant improvement in survival times compared to OptisolTM and TID 0.9% NaCl controls. Cornea storage in 1mg/ml AVI-5126 + post transplant treatment increased survival time from 5.6+-0.79 days to 7.0 + 1.21 days (mean+ standard deviation, n=9, p<0.05), while storage in 0.5 mg/ml AVI-5126 + post transplant treatment increased survival time to 7.0+1.7 days (n=3, p<0.05).

Conclusions: : This rat model of in vivo corneal transplantation shows significant delay in graft rejection by storing donor corneas followed by topically treating graft recipients with new, highly stable antisense drugs. This improvement occurs without the local or systemic immunosuppression seen in rejection models treated with local or systemic cyclosporine. In addition, these anti-sense agents can be successfully applied topically without irritation or local toxicity.

Keywords: cornea: basic science • transplantation • cornea: storage 
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