Oral levodopa rescues retinal morphology and visual function in a murine model of human albinism

Abstract

Albinism is a group of disorders characterized by pigment deficiency and abnormal retinal development. Despite being a common cause for visual impairment worldwide, there is a paucity of treatments and patients typically suffer lifelong visual disability. Residual plasticity of the developing retina in young children with albinism has been demonstrated, suggesting a post-natal window for therapeutic rescue. L-3, 4 dihydroxyphenylalanine (L-DOPA), a key signalling molecule which is essential for normal retinal development, is known to be deficient in albinism. In this study, we demonstrate for the first time that post-natal L-DOPA supplementation can rescue retinal development, morphology and visual function in a murine model of human albinism, but only if administered from birth or 15 days post-natal age.

Keywords: albinism; levodopa; neuronal plasticity; ocular; retina; therapeutics; vision.

Figure 1

Example mean electroretinogram recordings from CALBs (a) and B6 (b) mice supplemented with L‐DOPA 1 mg/ml from birth, 15 and 28 days PNA, in comparison with untreated controls, at 6 weeks PNA. A more negative A‐wave amplitude (reflecting photoreceptor function) and a more positive B‐wave amplitude (reflecting inner retinal function) reflect better retinal function. There were significant (p < 0.001) increases in the A‐ and B‐wave amplitudes of the CALBs mice supplemented with L‐DOPA from birth and 15 days PNA in comparison with untreated controls. B6, C57BL/6 pigmented mice; CALBs, C57BL/6J‐c2J OCA mice; OCA, oculocutaneous albinism; PNA, post‐natal age

Figure 2

Electroretinogram results summarizing the A‐ (a) & (b) and B‐wave (c) & (d) amplitudes recorded from CALBs (a) & (c) and B6 (b) & (d) mice treated with L‐DOPA from birth, 15 and 28 days PNA, in comparison with untreated controls. The upper plots for each panel show the A‐ and B‐wave amplitudes plotted with respect to post‐natal age. Each point represents a single value from each ERG examination. The lines of best fit (trend lines) are shown in navy for the control mice, and maroon, green and orange for the mice treated from 28 days PNA, 15 days PNA and birth, respectively. The lower plots for each panel are marginal effects plots summarizing the average differences in A‐ and B‐wave amplitudes, between each of the three treatment groups in comparison to untreated controls (y = 0), with respect to post‐natal age. The error bars are representing the 95% confidence intervals. By calculating partial derivatives of the interaction term from the linear mixed model, the significant differences between each of the three treatment groups and the control groups were estimated at six specified time points: 28, 35, 42, 56, 82 and 112 days PNA. B6, C57BL/6 pigmented mice; CALBs, C57BL/6J‐c2J OCA mice; ERG, electroretinogram; OCA, oculocutaneous albinism; PNA, post‐natal age

Figure 3

Example of in vivo optical coherence tomography (OCT) retinal imaging obtained from untreated C57BL/6J‐c2J (CALB) (b) & (d) and C57BL/6 pigmented (B6) mice (c) and a CALB mouse supplemented with a 28‐day course of oral L‐DOPA from 15 days PNA (e). The en fosse view (a) is shown with the 24 segmentation locations surrounding the optic nerve highlighted in white. The circle is highlighting the central 17° retinal area surrounding the optic nerve, where the OCT segmentation analysis was focused. The arrows in (e) indicate the effects or oral L‐DOPA supplementation on each of the individual retinal layer thicknesses in comparison with untreated CALBs. The up and down arrows are indicating significant increases and decreases, respectively, in retinal layer thickness measurements. The lack of pigment in the CALB retina facilitates deeper penetration of the OCT through the RPE, artificially creating the appearance of a thicker choroid. B6, C57BL/6 pigmented mice; CALBs, C57BL/6J‐c2J OCA mice; ETPRS, photoreceptor end tips; GCL‐IPL, combined ganglion cell‐inner plexiform layer complex; INL, inner nuclear layer; IS, photoreceptor inner segment; OCA, oculocutaneous albinism; ONL, outer nuclear layer; OPL, outer plexiform layer; OS, photoreceptor outer segment; RNFL, retinal nerve fibre layer; RPE, retinal pigment epithelium

Figure 4

Graphs of the relationship between A‐wave amplitudes and RNFL (a), OPL (b), OS (c), ETPRS (d) and RPE (e) OCT thickness measurements. The best fit linear line together with its 95% confidence interval is shown. Spearman's rho (rs) is shown, together with the Bonferroni adjusted p value. Significant values are indicated in bold text. See Figure S4 to view the individual data, colour coded based on treatment group. ETPRS, photoreceptor end tips; OCA, oculocutaneous albinism; OCT, optical coherence tomography; OPL, outer plexiform layer; OS, photoreceptor outer segment; RNFL, retinal nerve fibre layer; RPE, retinal pigment epithelium

Figure 5

Graphs of the relationship between B‐wave amplitudes and RNFL (a), OPL (b), OS (c), ETPRS (d) and RPE (e) OCT thickness measurements. The best fit linear line together with its 95% confidence interval is shown. Spearman's rho (rs) is shown, together with the Bonferroni adjusted p value. Significant values are indicated in bold text. See Figure S4 to view the individual data, colour coded based on treatment group. ETPRS, photoreceptor end tips; OCA, oculocutaneous albinism; OCT, optical coherence tomography; OPL, outer plexiform layer; OS, photoreceptor outer segment; RNFL, retinal nerve fibre layer; RPE, retinal pigment epithelium