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-9364448-B2
Publication Date
2016-06-14
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 the treatment of vision problems and increased pigmentation in subjects suffering from various forms of albinism, including oculocutaneous albinism types OCA1a and OCA1b, ocular albinism type 1, and forms of albinism resulting from mutations in the GPR143, OCA2, OCA3, or OCA4 genes. This is achieved by administering a pharmaceutical composition containing a therapeutically effective amount of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione). The administration elevates tyrosine plasma concentrations, which increases tyrosinase activity and subsequently pigmentation in eye tissues and other tissues such as skin and hair.
Albinism is a congenital disorder characterized by the absence or defect of enzymes involved in melanin production, leading to lack of pigment in skin, hair, and eyes, and causing significant visual disability. Existing treatments are limited to managing refractive errors and visual aids, with no effective methods to restore pigmentation or substantially improve vision. Particularly, oculocutaneous albinism, which affects eyes, skin, and hair, and ocular albinism, which affects primarily the eyes, present untreated visual impairments such as nystagmus and photophobia.
The invention addresses the need to improve treatment of patients suffering from albinism by administering NTBC, an FDA-approved drug that blocks tyrosine degradation, increasing tyrosine levels in plasma. Increased tyrosine levels serve as a molecular chaperone, stabilizing mutant forms of tyrosinase, enhancing enzymatic activity and melanin production, specifically in individuals with residual tyrosinase activity. The method can be used to treat vision impairments caused by albinism and to increase pigmentation in eyes, hair, and skin for therapeutic or cosmetic purposes.
Claims Coverage
The patent includes one independent claim encompassing methods of increasing pigmentation in subjects by administering NTBC with specific dosage ranges and resulting plasma tyrosine concentrations.
Method of increasing visually discernible pigmentation in the iris
Administering a pharmaceutical composition comprising NTBC or its pharmaceutically acceptable salt, hydrate, or solvate with a physiologically acceptable carrier, in an amount effective to increase the number of pigmented melanosomes in the iris, thereby increasing visually discernible pigmentation.
Increasing plasma tyrosine concentrations
The method involves increasing plasma concentrations of tyrosine in the subject from about 7 μM to about 2 mM, or from about 50 μM to about 300 μM, or to at least about 70 μM to achieve pigmentation effects.
Administering specific dosage ranges of NTBC
NTBC is administered in therapeutically effective 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 about 1 mg/kg/day to about 2 mg/kg/day, most preferably about 1 mg/kg/day.
Treatment of albinism types and genetic causes
The method is applicable to subjects suffering from oculocutaneous albinism (types OCA1a and OCA1b), ocular albinism type 1, and albinisms due to mutations in tyrosinase, GPR143 gene, P protein gene (OCA2), tyrosinase-related protein-1 (TYRP-1, OCA3), and microtubulin associated protein tau (MATP, OCA4) genes.
Use for cosmetic pigmentation increase
The method includes increasing visually discernible pigmentation in the iris for cosmetic purposes.
The independent claim covers methods for increasing pigmentation in the iris and treating visual impairment associated with various forms of albinism by administering NTBC at specified dosages effective to elevate plasma tyrosine levels and increase pigmented melanosomes, applicable for both therapeutic and cosmetic uses.
Stated Advantages
Administration of NTBC can increase pigmentation in eye tissues, hair, and skin, thereby potentially alleviating symptoms caused by lack of pigmentation in albinism.
Increasing pigmentation via NTBC treatment can improve vision-related symptoms such as glare and light sensitivity in patients with albinism.
The method can be employed prenatally and postnatally to increase pigmentation without obvious adverse effects.
NTBC is an FDA-approved drug with known safety profiles, enabling its repurposing for albinism treatment.
Documented Applications
Treatment of vision problems in subjects suffering from oculocutaneous albinism types OCA1a and OCA1b, ocular albinism type 1, and albinisms due to mutations in GPR143, OCA2, OCA3, and OCA4 genes.
Administration of NTBC to increase pigmentation in the eyes, hair, and skin of subjects for cosmetic purposes.
Use in prenatal and neonatal treatment to enhance pigmentation development in offspring with albinism mutations.
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