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Ighovie F. Onojafe, David R. Adams, Jun Zhang, Chi-Chao Chan, Isa M. Bernardini, Yuri V. Sergeev, Monika B. Dolinska, William A. Gahl, Brian P. Brooks; Nitisinone (NTBC) Improves Ocular and Skin Pigmentation Defects In a Mouse Model of Oculocutaneous Albinism. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2357.
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Oculocutaneous albinism (OCA) is an autosomal recessive condition characterized by reduced pigmentation of the skin, hair, and eyes; decreased best-corrected visual acuity; foveal hypoplasia; abnormal decussation of optic nerve fibers; and nystagmus. The relationship, if any, between ocular pigmentation and visual development is not well understood. However, because foveal maturation occurs largely postnatally and because ocular pigment may reduce symtoms of glare sensitivity, improving pigmentation may potentially improve visual function. The most common genetic type of OCA in North America is OCA1, caused by mutations in the rate-limiting and essential enzyme in pigment synthesis, tyrosinase (Tyr). We postulated that increasing plasma tyrosine concentrations using the FDA-approved drug, NTBC, might stabilize tyrosinase and improve pigmentation in mouse models of OCA1.
Two mouse models of OCA1 were tested: 1) C57BL/6-Tyr c-2J/c-2J (c-2J) are phenotypically albino (white coat, pink eyes) due to a c.G291T (p.R77L) mutation in the Tyr gene that is functional null at the protein level - a model of OCA1a where no pigment is present and 2) C57BL/6Tyrc-h/c-h (c-h) have a temperature sensitive allele of Tyr (c.A1259G, p.H420R) such that their eyes are pink,their coat color is off-white and their extremities are lightly pigmented - a model of OCA1B, where Tyr is partially functional & some pigment is present. NTBC or vehicle was given qod via oral gavage at 4mg/kg for 1 month to each group. Plasma tyrosine levels (PTL) were measured. Coat color and ocular pigmentation were assessed clinically, histologically, & using electron microscopy (EM).
PTLs were elevated in both strains of treated - but not control - mice. Whereas c-2J mice did not develop significant pigmentation on NTBC treatment, c-h mice develop visible pigmentation in their hair and irides. Furthermore, EM of iris, RPE, and choroid of treated c-h mice shows a significant increase in pigmented melanosomes.
NTBC treatment elevates PTLs in 2 mouse models of OCA. Clinically significant changes in ocular & coat pigmentation were observed in treated c-h mice after 1 month of treatment. Because NTBC is an FDA-approved drug for the treatment of human tyrosinemia, type 1, these results are encouraging support for a pilot study of NTBC treatment in human OCA1b.
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