September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
In vivo protection of degenerating cones in the cpfl1 mouse by HDAC inhibition
Author Affiliations & Notes
  • Dragana Trifunovic
    Institute for Ophtalmic Research, University-Eye-Clinic Tuebingen, Tuebingen, Germany
  • Anotella Comitato
    University of Modena and Reggio Emilia, Modena, Italy
  • Blanca Arango-Gonzalez
    Institute for Ophtalmic Research, University-Eye-Clinic Tuebingen, Tuebingen, Germany
  • Melanie Barth
    Institute for Ophtalmic Research, University-Eye-Clinic Tuebingen, Tuebingen, Germany
  • Eva María del Amo Páez
    University of Helsinki, Helsinki, Finland
  • Arto Urtti
    University of Helsinki, Helsinki, Finland
    University of Eastern Finland, Kuopio, Finland
  • Yvan Arsenijevic
    Jules-Gonin Eye Hospital, Lausanne, Switzerland
  • Marius Ueffing
    Institute for Ophtalmic Research, University-Eye-Clinic Tuebingen, Tuebingen, Germany
  • Valeria Marigo
    University of Modena and Reggio Emilia, Modena, Italy
  • Francois Paquet-Durand
    Institute for Ophtalmic Research, University-Eye-Clinic Tuebingen, Tuebingen, Germany
  • Footnotes
    Commercial Relationships   Dragana Trifunovic, None; Anotella Comitato, None; Blanca Arango-Gonzalez, None; Melanie Barth, None; Eva del Amo Páez, None; Arto Urtti, None; Yvan Arsenijevic, None; Marius Ueffing, None; Valeria Marigo, None; Francois Paquet-Durand, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4393. doi:
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      Dragana Trifunovic, Anotella Comitato, Blanca Arango-Gonzalez, Melanie Barth, Eva María del Amo Páez, Arto Urtti, Yvan Arsenijevic, Marius Ueffing, Valeria Marigo, Francois Paquet-Durand; In vivo protection of degenerating cones in the cpfl1 mouse by HDAC inhibition. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4393.

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

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Abstract

Purpose : Recent evidence indicates that photoreceptor cell death in inherited retinal degeneration is governed by non-apoptotic mechanisms (Arango-Gonzalez et al., Plos One., 9(11):e112142, 2014). These mechanisms involve an over-activation of histone deacetylase (HDAC) and are also driving primary cone death in the cone-photoreceptor-function-loss (cpfl1) mouse. In the present study, we investigated whether HDAC inhibition could prevent cpfl1 cone loss in vivo.

Methods : Cpfl1 and wt animals (n=11 and n=6, respectively) were injected intravitreally, in one eye, at the onset of cone degeneration (PN14) with 1nM or 10nM Trichostatin A (TSA), an inhibitor of HDAC. The contralateral eye was sham-injected and served as a control. The effects of TSA were assessed by quantifying the percentage of cones in TSA-treated vs. sham-treated eyes at the peak of degeneration (PN24). In addition we investigated cone migration by measuring the cone migration distance within the ONL in treated and non-treated eyes.

Results : In vivo treatment with a single injection of two different TSA concentrations resulted in a significant improvement of cone survival in cpfl1 mice. The percentage of cones compared to the wt retinas in non-treated animals was ~80% (wt: 5.378% ± 0.38; cpfl1 sham: 4.57% ± 0.18 SEM), while in TSA treated the number of cones reached 96% of wt (cpfl1 treated: 5.374% ± 0.78, p= 0.027). HDAC inhibition had also a second effect on cones, as the treatment significantly improved impaired developmental cone migration from the OPL to the outer parts of the outer nuclear layer. In non-treated retinas cones migrated only to 71.68% ± 1.09 SEM of ONL thickness while in TSA treated cpfl1 retinas cones were positioned up to 77.18% ± 0.84, p=0.02, of ONL thickness, compared to 86.89% ± 0.26 SEM in wt retinas.

Conclusions : We show that pharmacological inhibition of HDAC can prevent hereditary cone photoreceptor degeneration and also partially restore the normal cone migration pattern. Importantly, a single injection afforded long-lasting protection. This highlights the feasibility of targeted neuroprotection in vivo, and creates hope to maintain vision in patients suffering from cone dystrophies and from diseases caused by improper cone migration.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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