April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Optic Nerve Regeneration Using AG1478 PLGA Constructs
Author Affiliations & Notes
  • R. Robinson
    Yale University, New Haven, Connecticut
  • J. Lin
    Yale Eye Center, New Haven, Connecticut
  • C. A. Williams
    Yale University, New Haven, Connecticut
  • J. M. Criscione
    Yale University, New Haven, Connecticut
  • S. R. Viviano
    Yale University School of Medicine, New Haven, Connecticut
  • J. C. Tsai
    Yale Eye Center, New Haven, Connecticut
  • E. B. Lavik
    Case Western Reserve University, Cleveland, Ohio
  • Footnotes
    Commercial Relationships  R. Robinson, USSN 61/260,522, P; J. Lin, None; C.A. Williams, None; J.M. Criscione, None; S.R. Viviano, None; J.C. Tsai, None; E.B. Lavik, USSN 61/260,522, P.
  • Footnotes
    Support  NIH NRSA F31EY019441, NIH Training Grant T90-DK070068, Kind gifts from Richard and Gail Siegal and Carol Sirot
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3800. doi:
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      R. Robinson, J. Lin, C. A. Williams, J. M. Criscione, S. R. Viviano, J. C. Tsai, E. B. Lavik; Optic Nerve Regeneration Using AG1478 PLGA Constructs. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3800.

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

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Purpose: : The epidermal growth factor receptor (EGFR) plays an important role in optic nerve regeneration. Therapeutic strategies that target inhibition of EGFR via tyrosine kinase inhibitors (TKIs) can promote significant nerve regeneration, but systemic administration of TKIs leads to adverse side effects. To facilitate local delivery, we developed and characterized poly(lactic-co-glycolic acid) (PLGA) micro- and nano-spheres delivering the EGFR TKI AG1478. We evaluated their ability to promote nerve regeneration in an optic nerve crush injury model.

Methods: : Micro- and nano-spheres were fabricated using a single emulsion. Sphere size, loading, release kinetics, and bioactivity were evaluated in vitro. The optic nerve of adult rats was crushed for 10s, followed by injection (i.e., sub-tenon or intravitreal) of micro- or nano-spheres containing AG1478, Coumarin-6--for tracking purposes--or no drug into the eye. Cholera toxin subunit B was intravitreally injected prior to animal sacrifice to trace regenerating fibers through the injury site. Animals were sacrificed at 1, 2, 3, 4, and 7 weeks and tissue was immunostained for markers of regeneration, gliosis, and immune reaction.

Results: : Microspheres (diameter = 2.56±1.90 µm) and nanospheres (diameter = 359±54.0 nm) delivered AG1478 for at least 105 days. Using western blot analysis it was determined that encapsulated AG1478 was as effective as non-encapsulated AG1478 in inhibiting activation of EGFR. Using fluorescent microscopy, Coumarin-6 microspheres were located proximal to the crush site up to seven weeks after injury. Early data suggests that the site of delivery targets different sources of axons. Intravitreal administration of AG1478 appears to promote regeneration of the RGCs through the crush injury site, while sub-tenon administration may promote regeneration of axons from other neuronal populations.

Conclusions: : AG1478 can be encapsulated in PLGA micro- and nano-spheres and retain its bioactivity. Spheres are capable of delivering AG1478 for at least 105 days, and administration of the spheres in a rodent model promotes nerve regeneration.

Keywords: regeneration • optic nerve • drug toxicity/drug effects 

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