July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Variability in therapeutic outcome due to age of P23H rhodopsin mice at time of dosing can be reduced by enhanced retinal drug delivery.
Author Affiliations & Notes
  • Anna-Sophia Kiang
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Paul Kenna
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Marian M Humphries
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Anh Nguyen
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • James Keaney
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Jane G Farrar
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Matthew Campbell
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Peter Humphries
    Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Anna-Sophia Kiang, None; Paul Kenna, None; Marian Humphries, None; Anh Nguyen, None; James Keaney, None; Jane Farrar, None; Matthew Campbell, None; Peter Humphries, None
  • Footnotes
    Support  Science Foundation Ireland S.F.I 11/PI/1080
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1013. doi:
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      Anna-Sophia Kiang, Paul Kenna, Marian M Humphries, Anh Nguyen, James Keaney, Jane G Farrar, Matthew Campbell, Peter Humphries; Variability in therapeutic outcome due to age of P23H rhodopsin mice at time of dosing can be reduced by enhanced retinal drug delivery.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1013.

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

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Abstract

Purpose : Retinitis Pigmentosa (RP), is currently incurable and while many compounds have been shown to retard retinal degeneration in animal models of RP, the effect of age and thus extent of disease progression at time of dosing is often overlooked. This has direct implications for RP patients. Here, we investigate whether the age at which P23H-knockin rhodopsin (P23H) mice are administered an hsp90 inhibitor can result in variability of therapeutic outcome and, if so, whether increasing drug delivery to retina via transient modulation of the inner blood retina barrier (iBRB) can significantly reduce this variability in addition to retarding retinal degeneration.

Methods : Cohorts of heterozygous P23H mice (n=4) were dosed with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) at 2mg/Kg/day in drinking water either from P20 or P35 to P62. Retinal function was examined by electroretinography (ERG) at P64 and retinal structure analysed by optical coherence tomography (OCT) or histology. A pharmacokinetic study was carried out on one cohort following i.p. injection of 8mg/Kg 17-DMAG and retinal 17-DMAG content quantified by mass spectrometry. Transient iBRB modulation was carried out following subretinal injection of a doxycycline-inducible AAV2/9 construct expressing shRNA targeting the tight junction protein claudin-5, in cohorts of P23H mice (n=6) and albino hemizygous P23H-line 3 rat (n=10).

Results : P23H mice dosed from P20 with 17-DMAG exhibited preserved retinal function and structure (p=0.01) while those dosed from P35 responded variably (“responders” and “non-responders”). Results of a pharmacokinetic study showed that the “non-responder” mice had significantly lower retinal 17-DMAG concentrations (p<0.01). Transient iBRB modulation allowed enhanced delivery of 17-DMAG (6mg/Kg/week, 4 weeks) to P35 P23H mice which significantly enhanced retinal function and reduced variability in therapeutic outcome (p<0.05). Similarly enhanced 17-DMAG delivery to P23H rat retina also retarded degeneration (p<0.05).

Conclusions : Our results indicate that the age of P23H mice at which the 17-DMAG dosing regime begins has a significant bearing on therapeutic outcome variability. Furthermore enhancing drug uptake to the retina by transient iBRB modulation significantly reduces this variability in addition to retarding retinal degeneration in 2 rodent models of RP.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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