Nitisinone for treatment of oculocutaneous/ocular albinism and for increasing pigmentation
Inventors
Brooks, Brian P. • Gahl, William A.
Assignees
US Department of Health and Human Services
Publication Number
US-8822540-B2
Publication Date
2014-09-02
Expiration Date
2031-02-25
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Abstract
A method is provided for the treatment of vision problems in a subject suffering from one of various forms of albinism, including, for example, oculocutaneous albinism types OCA1a and OCA1b, as well as ocular albinism type 1, resulting from mutations in the GPR143 gene, as well as the OCA2, OCA3 or OCA4 genes, by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the compound (2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione), also known as NTBC for a sufficient period of time. The administration of NTBC is believed to increase the amount of pigmentation in the subject and alleviate certain symptoms caused by lack of pigmentation in the eye tissues. Also described are methods of use of NTBC for increasing the pigmentation of a subject for cosmetic purposes, by administering to the subject a therapeutically effective amount of NTBC.
Core Innovation
The invention provides a method for treating vision problems in subjects suffering from various forms of albinism, including oculocutaneous albinism types OCA1a and OCA1b, as well as ocular albinism type 1 caused by mutations in genes such as GPR143, OCA2, OCA3, and OCA4. This treatment involves administering a pharmaceutical composition containing a therapeutically effective amount of the compound 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione, known as NTBC (nitisinone), for a sufficient period of time. Administration of NTBC increases the amount of pigmentation in the subject and alleviates symptoms caused by lack of pigmentation in eye tissues.
Albinism is a congenital disorder characterized by complete or partial absence of pigment in skin, hair, and eyes due to absence or defect in enzymes involved in melanin production. Oculocutaneous albinism (OCA) affects pigmentation in the eyes, skin, and hair to varying degrees and is categorized into types 1, 2, and 3, with OCA1 caused by mutations in the tyrosinase gene. Patients with albinism experience significant visual disabilities including foveal hypoplasia, nystagmus, photophobia, refractive errors, and abnormal optic nerve development. Current treatments focus on managing symptoms but are limited in improving vision.
Nitisinone (NTBC) is an FDA-approved drug for treating type 1 tyrosinemia by blocking tyrosine degradation, resulting in increased plasma tyrosine levels. The invention discovers that administering NTBC to subjects with certain forms of albinism leads to increased tyrosine levels, enhanced tyrosinase activity, and increased pigmentation. This approach can increase pigmentation in the eyes, hair, and skin, potentially improving visual function and serving cosmetic purposes. Methods include administering NTBC in effective amounts to achieve plasma tyrosine concentrations ranging from about 7 μM to about 2 mM, with dosages generally between 0.1 mg/kg/day and 10 mg/kg/day.
Claims Coverage
The patent claims encompass one independent claim that defines a method of treating impaired vision in subjects with various types of albinism using a pharmaceutical composition containing NTBC. The main inventive features focus on the composition, dosage, targeted forms of albinism, and effects on pigmentation and vision.
Use of NTBC to treat impaired vision in albinism
Administration of a pharmaceutical composition comprising NTBC or its pharmaceutically acceptable salt, hydrate, or solvate, together with a physiologically acceptable carrier, to increase the number of pigmented melanosomes in retinal pigment epithelium cells and treat impaired vision in subjects suffering from oculocutaneous albinism or ocular albinism.
Increasing plasma tyrosine concentrations to prescribed levels
Increasing plasma tyrosine concentrations in the subject from about 7 micromolar to about 2 millimolar, or specifically from about 50 μM to about 300 μM, or achieving plasma tyrosine concentrations of about 70 μM or higher by administration of NTBC.
Administering defined dosage ranges of NTBC
Administering NTBC to the subject in dosage amounts ranging from about 0.1 mg/kg/day to about 10 mg/kg/day, preferably between about 0.5 mg/kg/day to about 4 mg/kg/day, or more preferably about 1 mg/kg/day to about 2 mg/kg/day.
Treatment of specific types of oculocutaneous and ocular albinism
Applying the method to subjects with oculocutaneous albinism types OCA1a or OCA1b, as well as type 1 ocular albinism, including albinism due to mutations in the tyrosinase gene, the GPR143 gene, the P protein gene (OCA2), the tyrosinase-related protein-1 gene (OCA3), and the microtubulin associated protein tau gene (OCA4).
Increasing pigmentation for cosmetic or clinical benefits
Increasing visually discernible pigmentation in the eyes, hair, or skin of the subject and specifically increasing pigmentation or pigmented melanosomes in the iris or choroid of the eyes, as part of treating impaired vision or for cosmetic purposes.
The claims collectively define a method of treating impaired vision in albinism by administering NTBC in effective amounts to increase plasma tyrosine and pigmentation, covering various albinism types and specifying effective dosage ranges and pigmentation outcomes.
Stated Advantages
Administration of NTBC increases circulating tyrosine levels, promotes tyrosinase activity, and results in increased pigmentation in the eyes, hair, and skin of subjects with albinism.
Improves visual function by reducing symptoms such as glare and light sensitivity, which are greatly appreciated by patients suffering from albinism-associated vision problems.
NTBC use is applicable to multiple types of albinism, including oculocutaneous albinism (OCA1a, OCA1b) and ocular albinism type 1, and potentially other forms resulting from different gene mutations.
The method can increase pigmentation for both therapeutic (improving impaired vision) and cosmetic purposes.
Documented Applications
Treatment of vision problems in subjects suffering from oculocutaneous albinism types OCA1a and OCA1b, and ocular albinism type 1.
Increasing pigmentation in the eyes, hair, and skin of subjects for cosmetic purposes.
Treatment of subjects with albinism due to mutations in tyrosinase gene, GPR143 gene, P protein gene (OCA2), tyrosinase-related protein-1 gene (OCA3), and microtubulin associated protein tau gene (OCA4).
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