One-year pilot study on the effects of nitisinone on melanin in patients with OCA-1B

M. Roselle Abraham ,Angel Garced,Shôsuke Itô ,Kazumasa Wakamatsu,Melissa A. Merideth,Zaheer Valivullah ,Pei‐Wen Chiang ,Brett G. Jeffrey,David R. Adams,Wendy J. Introne,Brian P. Brooks,Supriya Menezes,Ramon Jauregui,Edythe Wiggs,Denise Cunningham,Shanna Bernstein,Rhona M. Jack,William A. Gahl,Ramakrishna P. Alur,Bradley Power

doi:10.1172/jci.insight.124387

Abstract

BACKGROUND. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene.METHODS. In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals.RESULTS. The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically.CONCLUSION. Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials.TRIAL REGISTRATION. ClinicalTrials.gov NCT01838655.FUNDING. Intramural program of the National Eye Institute.

Highlights

Oculocutaneous albinism (OCA) is a genetically heterogeneous, autosomal recessive condition characterized by absent or reduced melanin pigment in the eyes, hair, and skin [1,2,3]
Melanins are complex biomolecules made in melanocytes and the retinal pigment epithelium (RPE) and stored in subcellular organelles called melanosomes
We have demonstrated that small doses of oral nitisinone in OCA-1B mice fed ad libitum increases plasma tyrosine and increases melanin pigmentation in the fur and eyes [21]

Summary

Introduction

Oculocutaneous albinism (OCA) is a genetically heterogeneous, autosomal recessive condition characterized by absent or reduced melanin pigment in the eyes, hair, and skin [1,2,3]. Melanins are complex biomolecules made in melanocytes and the retinal pigment epithelium (RPE) and stored in subcellular organelles called melanosomes. They can be divided into two broad biochemical categories: eumelanin (brown-black melanin) and pheomelanin (red-brown melanin, which contains sulfur atoms). Albinism are the direct or indirect result of reduced tyrosinase activity in the melanosome. Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene

Methods

Results

Conclusion