Oral human-equivalent L-DOPA/Carbidopa dosages administered during the postnatal critical period of neuroplasticity rescues retinal morphology and visual function in a mouse model of human albinism

Abstract

Purpose : Evidence of ongoing retinal development in children with albinism has been demonstrated. L-DOPA, a key molecule for the correct development of the retina, is known to be deficient in the developing albino eye, resulting in abnormalities of retinal structure and visual impairment. Thus, we investigated if human equivalent doses of L-DOPA/Carbidopa (i.e. doses established for the treatment of infantile dystonia and amblyopia), can rescue visual function in a mouse model of human oculocutaneous albinism (OCA), if administered during the postnatal critical period of neuroplasticity.

Methods : C57BL/6J (B6; n=24) and C57BL/6J-c2J OCA (CALBs; n=10) mice were treated with a 28-day course of oral L-DOPA/Carbidopa 9.4/2.3 mg/kg, from 15 to 43 days postnatal age (PNA) and compared to untreated B6 mice (n=8) and CALBs (n=16). Retinal morphology and function were assessed at 6 weeks PNA using optical coherence tomography and electroretinography. Photopic spatial frequency thresholds (i.e. visual acuity) were assessed by optokinetic nystagmus using an OptoMotry system at 7 weeks PNA.

Results : At 6 weeks PNA, the outer nuclear layer (ONL) thickness of untreated CALBs was significantly increased (61.5±0.2 vs 66.6±0.2 μm; p=0.0004). The ONL of treated CALBs (61.9±0.2 μm) recovered the same thickness found in B6 mice (61.3±0.3μm; p=0.779). A- and B-wave amplitudes were significantly diminished in untreated CALBs (284±18 vs 176±15 μV; p=0.0033; and -136±19 vs -85±9 μV; p=0.0298). Treated CALBs recovered amplitudes similar to B6 mice (340±16 and -183±9 μV, respectively). Photopic spatial frequency thresholds, were significantly lower in untreated CALBs; clock-wise (CW) (0.458±0.059 vs 0.188±0.095 c/d; p=0.0038) and clock-counter-wise (CCW) (0.401±0.012 vs 0.107±0.001 c/d; p=0.0012). Both thresholds improved in treated CALBs, reaching comparable levels to B6 mice (CW: 0.419±0.021 vs 0.292±0.026 c/d; p=0.1009; and CCW: 0.382±0.027 vs 0.330±0.044 c/d, respectively; p=0.5778).

Conclusions : Our results demonstrate that human equivalent doses of oral L-DOPA/Carbidopa supplementation during the critical postnatal period of retinal neuroplasticity can rescue visual function and retinal morphology in a mouse model of albinism. This novel work brings an effective treatment for children with albinism one step closer.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.