Pre-clinical studies of NTBC as a potential treatment for albinism

NTBC 作为白化病潜在治疗方法的临床前研究

• 批准号: 8339790
• 负责人: Brian Brooks
• 金额: $ 32.78万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8339790
• 关键词: Adult; Adverse effects; Albinism; Amblyopia; Animal Model; Award; Axon; Blindness; Child; Choroid; Clinical; Clinical Research; Clinical Trials; Color; Computer Simulation; Deposition; Drug usage; Early treatment; Electron Microscopy; Enzymes; Eye; FDA approved; Female; Funding; Fundus; Glare; Goals; Grant; Hair; Heating; Human; Hypopigmentation; In Vitro; Iris; Journals; Kinetics; Limb structure; Melanins; Melanogenesis; Melanosomes; Missense Mutation; Modeling; Monophenol Monooxygenase; Mus; Mutation; Oculocutaneous Albinism; Oculocutaneous albinism type 1; Operative Surgical Procedures; Optic Chiasm; Outcome; Pathologic Nystagmus; Patients; Pharmaceutical Preparations; Photophobia; Pigmentation physiologic function; Pigments; Plasma; Proteins; Publications; Refractive Errors; Research; Residual state; Role; Skin; Staging; Structure of retinal pigment epithelium; Testing; Therapeutic; Translating; Tyrosine; Tyrosinemias; United States National Institutes of Health; Vision; Visual impairment; Visual system structure; Work; blind; dopaquinone; experience; ganglion cell; improved; in vivo; infancy; macula; mutant; orbit muscle; preclinical study; pup; research study; small molecule; vision aid

We used Tyr c-2J/c-2J as a model for OCA1a. These mice are white with pink eyes due to a missense mutation in tyrosinase that is null at the protein level. We used Tyr c-h/c-h (Himalayan) mice as our model of OCA1b. These mice have an off-white coat color, reduced ocular pigmentation and pigmentation in their extremities due to a mutation that produces a heat-labile form of tyrosinase. We successfully obtained independent grant funding from the Blind Childrens Center for our pilot experiments. Nitisinone treatment resulted in a 6-fold and a 4-fold increase in steady-state plasma tyrosine concentrations in Tyrc-2J/c-2J and Tyrc-h/c-h mice, respectively. After one month of nitisinone treatment, C57BL6-Tyr c-h/ch mice, but not C57BL6-Tyr c-2J/c-2J mice, showed a visible increase in coat and iris pigmentation. Neither vehicle-treated group showed any change in pigmentation. (Because pigment is preferentially deposited in growing hair, a patch of each mouses coat was shaved immediately prior to initiating nitisinone treatment.) Electron microscopy studies revealed a statistically-significant difference in the number of pigmented (stage III and IV) melanosomes in the RPE, choroid and iris of treated C57BL6-Tyr c-h/ch mice. No difference was observed in C57BL6-Tyr c-2J/c-2J mice or in vehicle treated mice. Maternal treatment during pregnany of Tyr c-h/c-h females leads to an increase in pigmentation of pups when they are born. We have performed both in silico and in vitro studies of the c-2J and c-h mutant proteins and demonstrated that the latter responds to increased tyrosine. This work has been accepted for publication in the Journal of Clinical Investigation. An NIH Director's Award Challenge Grant was received near the end of FY2011 to help proceed with this work.

我们使用 Tyr c-2J/c-2J 作为 OCA1a 的模型。 这些小鼠呈白色，眼睛呈粉红色，这是由于酪氨酸酶的错义突变导致蛋白质水平为零。 我们使用 Tyr c-h/c-h (喜马拉雅) 小鼠作为 OCA1b 模型。 这些小鼠的毛色呈灰白色，由于产生不耐热酪氨酸酶的突变，导致眼部色素沉着和四肢色素沉着减少。 我们成功地从盲人儿童中心获得了用于试点实验的独立拨款资金。 尼替西农治疗导致 Tyrc-2J/c-2J 和 Tyrc-h/c-h 小鼠的稳态血浆酪氨酸浓度分别增加 6 倍和 4 倍。 经过尼替西农治疗一个月后，C57BL6-Tyr c-h/ch 小鼠（而非 C57BL6-Tyr c-2J/c-2J 小鼠）表现出皮毛和虹膜色素沉着的明显增加。 媒介物处理组均未显示色素沉着的任何变化。 （由于色素优先沉积在生长的毛发中，因此在开始尼替西农治疗之前立即剃去每只小鼠皮毛的一小块。） 电子显微镜研究显示，经治疗的 C57BL6-Tyr c-h/ch 小鼠的 RPE、脉络膜和虹膜中色素沉着（III 期和 IV 期）黑素体的数量存在统计学显着差异。在 C57BL6-Tyr c-2J/c-2J 小鼠或载体处理的小鼠中没有观察到差异。 Tyr c-h/c-h 雌性怀孕期间的母体治疗会导致幼崽出生时色素沉着增加。 我们对 c-2J 和 c-h 突变蛋白进行了计算机模拟和体外研究，并证明后者对酪氨酸增加有反应。 这项工作已被接受发表在《临床研究杂志》上。 2011 财年末，我们收到了 NIH 院长挑战奖资助，以帮助开展这项工作。