HDAC inhibition in the cpfl1 mouse protects degenerating cone photoreceptors in vivo.
Cone photoreceptor cell death as it occurs in certain hereditary retinal diseases is devastating, with the affected patients suffering from a loss of accurate and colour vision. Regrettably, these hereditary cone diseases are still untreatable to date. Thus, the identification of substances able to block or restrain cone cell death is of primary importance. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cpfl1 cones in vitro, in retinal explant cultures. More importantly, in vivo, a single intravitreal TSA injection significantly increased cone survival for up to 16 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and retinal diseases associated with impaired cone migration.
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Dragana
D
Trifunović
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Blanca
B
Arango-Gonzalez
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Antonella
A
Comitato
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Melanie
M
Barth
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Eva M
EM
Del Amo
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Manoj
M
Kulkarni
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Ayse
A
Sahaboglu
Research Unit Protein Science, Helmholtz Center Munich, Neuherberg, Germany.
Stefanie M
SM
Hauck
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Centre for Drug Research, Division of Pharmaceutical Bioscience, University of Helsinki, Helsinki, Finland.
Arto
A
Urtti
Unit of Gene Therapy & Stem Cell Biology, Hôpital Ophtalmique Jules Gonin, University of Lausanne, Lausanne, Switzerland.
Yvan
Y
Arsenijevic
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Marius
M
Ueffing
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Valeria
V
Marigo
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
François
F
Paquet-Durand
D000818:Animals; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects* / Q000473:pathology*; D012162:Retinal Degeneration / Q000188:drug therapy*
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; C012589:trichostatin A