Our previously-reported work on OCA1A and OCA1B mouse models has been published in the Journal of Clinical Investigation. This work established the nitisinone could increase melanin pigmentation in a mouse model of OCA1B, but not OCA1A. Since the time of the last report, we have focused on the following sub-project: 1. Visual function in NTBC-treated OCA1B mice vs. controls We have evaluated the effect of nitisinone treatment on the retinal and visual function using several approaches. In collaboration with Dr. Qian, we have characterized the effect of nitisinone treatment on the full-field ERG (scotopic and photopic). In collaboration with members of Dr. Anand Swaroop's group we are assessing the effect of prenatal/early postnatal nitisone treatment on neurla retina development. In collaboration with Dr. Tudor Badea's group, we have studied the effect of nitisinone treatment on spatial visual acuity and on neural circuit development. We are currently preparing a manuscript for publication. 2 Effect of nitisinone on a mouse model of OCA3 We hypothesized that nitisinone might improve melanization in a mouse model of OCA3 (the Tyrp1-brown mouse), as tyrosinase and TYRP-1 are known to interact and stabilize one another in the melanosome membrane. The mouse received from Jackson Labs appears to harbor a novel nonsense allele of Tyrp1, rather than the canonical brown allele. We have studied the effect of nitisinone treatment on fur and eye pigmentation clinically and have studed its effect on melanosome number/area in the pigmented tissues of the OCA3 mouse eye. These data are being prepared for publication. 3. Effect of nitisinone on a mouse model of OCA4 We hypothesized that nitisinoen might improve melanization in a mouse model of OCA4(the so-called underwhite allele of SLC45A2). The mice received from Jackson Lab, although they all harbor the classic underwhite allele, demonstrateed two distinct coat colors (light and dark)when bred to homozygosity. We are currently evaluating the characteristics of melanized cells in both varieties of OCA4 mouse and are using high-throughput sequencing to identify the second, modifying allele. Simultaneously, we are also conducting treatment experiments to determine if nitisinone will improve ocular/fur pigmentation in both sub-strains of this model 4. Use of topical nitisinone and Xalatan in ocular pigmentation We are currently determining whether nitisinone, when delivered as a topical eye drop, is capable of improving melanin content in the eyes of Himalayan (OCA1B) mice. In parallel, we are also testing the FDA-approved drug, Xalatan, which has been shown to increase iris pigmentation in patients taking this topical drop for glaucoma. 5. High-throughput drug screening to find compounds that regulate tyrosinase activity We have purified recombinant wild-type and mutant human tyrosinase in a larval expression system and performed detailed enzymology. These data have been published in PLoS ONE. We have established a fluorometric assay for measuring tyrosinase activity. In collaboration with NCATS, we are initiating a drug screen to identify compounds that may inhibit or enhance tyrosinase activity in vitro. We have developed a pipeline for validating targets, including in vitro studies of enzyme function and targeting. These screens will be followed by animal-based (i.e., zebrafish and, eventually, Himalayan mouse) screens. 6. Clinical Protocol for Studying the Effect of Nitisinone Treatment in Human Subjects with OCA1B We have established an IRB-approved protocol for the testing of a standard oral dose of nitisinone on ocular and systemic melanin pigmentation in patients with OCA1B. Since last year's report, we have fully enrolled all five patients with OCA1B and begun treatment. No serious adverse events have occurred. We are continuing to monitor treatment via predetermined outcome variables.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Wang, Chen; Brancusi, Flavia; Valivullah, Zaheer M et al. (2018) A novel iris transillumination grading scale allowing flexible assessment with quantitative image analysis and visual matching. Ophthalmic Genet 39:41-45
Bryan, Melanie M; Tolman, Nathanial J; Simon, Karen L et al. (2017) Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS. Mol Genet Metab 120:378-383
Simeonov, Dimitre R; Wang, Xinjing; Wang, Chen et al. (2013) DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum Mutat 34:827-35
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