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Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa.

Abstract
We studied the potential of systemically administered aminoglycosides as a therapy for retinal degeneration resulting from premature termination codon (PTC) mutations. Aminoglycosides were systemically delivered to two rodent models of retinal degeneration: a transgenic rat model of dominant disease caused by a PTC in rhodopsin (S334ter); and a mouse model of recessive disease (rd12) caused by a PTC in the retinoid isomerase Rpe65. Initial luciferase reporter assays were undertaken to measure the efficiency of gentamicin-induced read-through in vitro. These experiments indicated that gentamicin treatment induced on average a 5.3% extra read-through of the S334ter PTC in vitro, but did not affect the rd12 PTC. Beginning at postnatal day 5, animals received daily subcutaneous injections of gentamicin or geneticin at a range of doses. The effect of the treatment on retinal degeneration was examined by histopathology and electroretinography (ERG). Systemic treatment with aminoglycoside significantly increased the number of surviving photoreceptors in the S334ter rat model over several weeks of treatment, but was not effective in slowing the retinal degeneration in the rd12 mouse model. Similarly, ERG recordings indicated better preservation of retinal function in the treated S334ter rats, but no difference was observed in the rd12 mice. Daily subcutaneous injection of 12.5mug/g gentamicin was the only regimen that inhibited retinal degeneration without apparent adverse systemic side effects. Reduced effectiveness beyond postnatal day 50 correlated with reduced ocular penetration of drug as seen in gentamicin-Texas red (GTTR) conjugation experiments. We conclude that, in the rat model, an approximately 5% reduction of abnormal truncated protein is sufficient to enhance photoreceptor survival. Such a change in truncated protein is consistent with beneficial effects seen when aminoglycosides has been used in other, non-ocular animal models. In the rd12 mouse, lack of efficacy was seen despite this particular PTC being theoretically more sensitive to aminoglycoside modification. We conclude that aminoglycoside read-through of PTCs in vitro and in vivo cannot be predicted just from genomic context. Because there is considerable genetic heterogeneity amongst retinal degenerations, pharmacologic therapies that are not gene-specific have significant appeal. Our findings suggest that if adverse issues such as systemic toxicity and limited ocular penetration can be overcome, small molecule therapeutics, such as aminoglycosides, which target classes of mutation could hold considerable potential as therapies for retinal disease.
AuthorsK Guerin, C Y Gregory-Evans, M D Hodges, M Moosajee, D S Mackay, K Gregory-Evans, John G Flannery
JournalExperimental eye research (Exp Eye Res) Vol. 87 Issue 3 Pg. 197-207 (Sep 2008) ISSN: 1096-0007 [Electronic] England
PMID18644591 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Aminoglycosides
  • Carrier Proteins
  • Codon, Nonsense
  • Eye Proteins
  • Fluorescent Dyes
  • Gentamicins
  • Xanthenes
  • Texas red
  • Rhodopsin
  • antibiotic G 418
  • retinoid isomerohydrolase
  • cis-trans-Isomerases
Topics
  • Aminoglycosides (pharmacokinetics, therapeutic use)
  • Animals
  • Carrier Proteins (genetics)
  • Codon, Nonsense
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical (methods)
  • Electroretinography (drug effects)
  • Eye Proteins (genetics)
  • Fluorescent Dyes
  • Gentamicins (pharmacokinetics, therapeutic use)
  • Mice
  • Mice, Mutant Strains
  • Rats
  • Rats, Transgenic
  • Retina (metabolism)
  • Retinitis Pigmentosa (metabolism, pathology, prevention & control)
  • Rhodopsin (genetics)
  • Xanthenes
  • cis-trans-Isomerases

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