title: AAV-mediated gene replacement, either alone or in combination with physical and pharmacological agents, results in partial and transient protection from photoreceptor degeneration associated with betaPDE deficiency.
abstract: OBJECTIVE
  Mutations in the PDE6B gene cause recessive, severe retinitis pigmentosa (RP). PDE6B encodes the β subunit of the rod-specific phosphodiesterase (βPDE), which, when absent, results in toxic levels of intracellular Ca(2+) and photoreceptor cell death. Ca(2+) blockers, such as nilvadipine, as well as light restriction, slow photoreceptor degeneration in animal models of βPDE deficiencies. The goal of the study was to evaluate the efficacy of AAV2/5- or AAV2/8-mediated gene replacement in combination with nilvadipine and/or with light restriction in the rd10 mouse bearing homozygous pde6b mutations.
  
  
  METHODS
  AAV vectors encoding either βPDE or EGFP were subretinally administered at postnatal day (P)2. Nilvadipine was administered from P7 to P28. For light restriction, pregnant rd10 mice were kept in a dark environment until their pups were 28 days old. All functional and histologic analyses were performed at P35.
  
  
  RESULTS
  Significant morphologic photoreceptor protection was observed after subretinal administration of AAV vectors encoding EGFP. This protection further increased after administration of AAV2/8 or -2/5 encoding for βPDE and was not associated with significant functional improvement. Photoreceptor protection was higher after AAV2/8- than after AAV2/5-mediated delivery and was not significantly augmented by additional drug therapy and/or light restriction. The protective effect was lost after P35.
  
  
  CONCLUSIONS
  In conclusion, more efficient gene transfer tools than those used in this study, as well as a better understanding of the disease pathogenesis, should be explored to increase the effect of gene replacement and to design gene-based strategies that block the apoptotic pathways activated by βPDE deficiency.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Allocca
authors.forename: Anna
authors.initials: A
authors.lastname: Manfredi
authors.forename: Carolina
authors.initials: C
authors.lastname: Iodice
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Vicino
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D000818:Animals; D019556:COS Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D003624:Darkness; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006720:Homozygote; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D011247:Pregnancy; D012174:Retinitis Pigmentosa / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*
chemical_list: D002121:Calcium Channel Blockers; C035100:nilvadipine; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse; D009543:Nifedipine