Novel therapeutics for albinism

Abstract

Background: Albinism is a rare, inherited genetic disorder which affects 1:17,000 people worldwide. Due to disruption of the melanin synthesis pathway, albinism causes the loss of pigmentation in hair, skin, and eyes, which has detrimental consequences to the eyesight of affected individuals. Patients therefore present with conditions such as nystagmus, foveal hypoplasia, and strabismus. Previous work has demonstrated that early postnatal supplementation of Levodopa (L-DOPA), one of the key components of the melanin synthesis pathway, prevents vision loss in an albino mouse model. We hypothesise that L-DOPA does this by regulating currently unidentified downstream factors in the melanin synthesis pathway, or by affecting synaptogenesis in the retina. Unfortunately, L-DOPA is unlikely to be effective in all forms of albinism depending on where the melanin synthesis pathway is disrupted. Therefore, downstream factors may provide more effective treatment.

Aims: To investigate the effect of L-DOPA on synaptogenesis in albino and pigmented mice. To validate a known downstream factor, Pigment Epithelium Derived Factor (PEDF), as a potential therapeutic. Methods: Eyes from albino (CALBs) and pigmented (B6) mice given low, medium, and high doses of L-DOPA (0.5, 0.76 and 1 mg/kg TDS) were collected at 6, 12 and 16 weeks of age. Samples were snap frozen; paraffin embedded, and immunostained with synaptophysin. Frozen samples were also analysed via western blot to assess PEDF levels in response to LDOPA. Fluorescence intensity (FI) and densitometry were analysed via ImageJ. A mouse study was conducted with PEDF injected intravitreally into the eyes of CALB mice and their visual function and retinal morphology was measured via ERG, OCT and OptoMotry. Linear mixed modelling was then carried out on the data.

Results: Immunostaining showed that in pigmented and albino mice, different dosages of LDOPA caused a significant difference to the FI of the retinal plexiform layers. At high dosage in albino mice, L-DOPA caused diminished synaptic pruning, and a decrease in PEDF levels. Western blot analysis demonstrated that PEDF appears to act early in development. The mouse study demonstrated a significant effect of PEDF on the ERGs and OptoMotry results of treated CALB mice but no significant difference was seen in the OCT results.

Conclusions: Our work demonstrates that L-DOPA influences synaptogenesis and may alter PEDF levels in the developing retina. PEDF supplementation also results in a positive effect on the ERGs of albino mice. This suggests that PEDF may therefore improve vision in affected patients, but further experimentation is required to confirm this.

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Identifiers

ORCID for Sarah Lucy Macdonald: orcid.org/0000-0001-9287-0158

ORCID for Helena Lee: orcid.org/0000-0002-2573-9536

ORCID for Jay Self: orcid.org/0000-0002-1030-9963

ORCID for Arjuna Ratnayaka: orcid.org/0000-0002-1027-6938

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