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.