title: Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations.
abstract: Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6a (V685M/R562W) mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies.
authors.affiliation: Cell Death Mechanisms Group, Division of Experimental Ophthalmology, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Roentgenweg 11, Tuebingen 72076, Germany; Centre for Ophthalmology, The Second People's Hospital of Yunnan Province and The Fourth Affiliated Hospital of Kunming Medical University, Qingnian 176, Kunming 650021, China.
authors.forename: K
authors.initials: K
authors.lastname: Jiao
authors.affiliation: Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen , Tuebingen 72076, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sahaboglu
authors.affiliation: Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen 72076, Germany; Werner Reichardt Centre for Integrative Neuroscience (CIN), University of Tuebingen, Tuebingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Zrenner
authors.affiliation: Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen , Tuebingen 72076, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: Division of Ophthalmology, Department of Clinical Sciences, Lund, University of Lund , Lund 22184, Sweden.
authors.forename: P A R
authors.initials: PA
authors.lastname: Ekström
authors.affiliation: Cell Death Mechanisms Group, Division of Experimental Ophthalmology, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen , Roentgenweg 11, Tuebingen 72076, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Paquet-Durand