Abstract
Purpose: :
We have previously shown that systemic delivery of gentamicin to the TgN S334ter rat model of retinitis pigmentosa slowed the rate of retinal degeneration through ribosomal interference, allowing for read-though of the underlying genetic mutation. In addition, we have also shown that mouse embryonic stem (mES) cells secreting glial-derived neurotrophic factor (GDNF) affords neuroprotection to the retina and thereby slowed retinal degeneration in this same model. However, both these therapeutic approaches have a limited effect. We therefore hypothesized that by using a combination of both approaches, targeting different pathways, could have an additive effect and result in enhanced photoreceptor survival compared to monotherapy alone.
Methods: :
A subcutaneous injection of 12.5µg/gm gentamicin was given daily to S334ter rats from day P5 to P70. In a subset of these animals, cell suspensions containing approximately 200,000 mES cells and secreting approximately 35ng/106 cells/24 hours GDNF, were injected into the vitreous cavity at P21, without immunosuppression. Other (control) animals underwent intravitreal injection with an equal volume of vehicle. The effects of treatment was investigated by histopathology and outer nuclear layer (ONL) morphometry.
Results: :
At P70, the ONL cell counts in the peripheral retina of gentamicin only-treated rats was 50% of wildtype levels. This compared with 38% of wildtype in untreated S334ter controls (P < 0.05). In eyes that underwent only intravitreal injection of GDNF-expressing cells, the ONL cell count in the peripheral retina was 60% of wildtype counts (P < 0.05). In eyes that received both intravitreal injection of GDNF-expressing cells and systemic gentamicin treatment, the number of photoreceptor nuclei in the ONL of the peripheral retina was 75% of wildtype levels. Similar benefits were seen in cell counts taken in the central retina.
Conclusions: :
We demonstrate that in the TgN S334ter rat, the combination of systemic gentamicin treatment with intraocular injection of GDNF-secreting cells had a greater beneficial effect on retinal degeneration than seen with either of these monotherapies alone. These studies show that a combinatorial approach, targeting different points in the pathological process underlying disease can enhance photoreceptor survival above that seen with monotherapy.
Keywords: growth factors/growth factor receptors • photoreceptors • retinal degenerations: hereditary