Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism

Abstract

Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyr c-2J null allele or the Tyr c-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyr c-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyr c-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

“…[22] A recent study identified a potential therapeutic for OCA1 where some tyrosinase activity is present. Onojafe et al, [23] having noted that nitisinone (used in the treatment of hereditary tyrosinemia type 1) caused an increase in serum tyrosine levels, treated OCA1B mice with the drug and noted an improvement in pigmentation of the mice. [23] This is the first potential therapeutic treatment of OCA and may even be of use in prenatal treatment to prevent the optic tract misrouting that results in loss of visual acuity.…”

“…Onojafe et al, [23] having noted that nitisinone (used in the treatment of hereditary tyrosinemia type 1) caused an increase in serum tyrosine levels, treated OCA1B mice with the drug and noted an improvement in pigmentation of the mice. [23] This is the first potential therapeutic treatment of OCA and may even be of use in prenatal treatment to prevent the optic tract misrouting that results in loss of visual acuity. The effects of nitisinone on a developing fetus are not known; however, at least one patient has been reported to have had a successful pregnancy while taking nitisinone, [24] although no clinical studies have been performed to date.…”

Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism

“…Consistent with their hypothesis, Onojafe and colleagues found that administration of nitisinone at a dosage 2-4 times higher than used to treat HT-1 increased fur and eye pigmentation in OCA-1B mice (19). Treatment had no effect in OCA-1A mice, presumably because their misfolded tyrosinase is incapable of binding tyrosine.…”

“…Figure 2) and thus preventing accumulation of the toxic intermediates of tyrosine breakdown that cause the severe symptoms of HT-1. Inspired by this side effect (unlike typical drug repositioning), Onojafe and colleagues reasoned that administration of nitisinone to albino mice might result in elevated levels of tyrosine in tissues including RPE and epidermis (19), where it could then act (as in the hair bulb test) to rescue tyrosinase, presumably as a substrate chaperone. Substrate chaperones have been proposed for the treatment of genetic disorders including cystic fibrosis and Gaucher, Fabry, Tay-Sachs, and Sandhoff diseases.…”

“…Instead, correction would need to occur during the appropriate developmental window. To that end, Onojafe et al gave nitisinone to pregnant OCA-1B mice and found that pigmentation was augmented in their offspring (19). While correction of developmental ocular defects remains to be proven, the augmented melanogenesis that they observed during gestation is highly encouraging.…”