Neurosteroids in health and disease

描述（由申请人提供）： C型尼曼-匹克病（NP-C）是一种致死性常染色体隐性遗传儿童期神经退行性疾病，目前尚无治疗方法。它是一种溶酶体脂质储存疾病，其特征在于细胞内胆固醇的运输缺陷，以及未酯化胆固醇、神经节苷脂和其他脂质的溶酶体蓄积。神经系统中由胆固醇合成的神经类固醇影响神经元的生长和分化。我们最近发表的数据表明，在BALB/c NP-C小鼠中，胚胎后神经类固醇合成以时间和区域特异性方式改变，并且表达类固醇生成酶的神经元和神经胶质细胞在NP-C小鼠中丢失。特别地，GABA能神经类固醇别孕烯醇酮（ALLO）的合成在出生时当啮齿动物大脑仍在经历成熟时基本上减少，并且随着时间的推移进一步减少。我们推测这些神经类固醇生成的改变可能有助于临床表型。我们的数据表明，适当定时的ALLO治疗NP-C小鼠可延长NP-C小鼠的寿命，并延迟神经功能障碍的发作，这些神经功能障碍是这种疾病在小鼠中的标志-震颤、共济失调和后肢功能障碍。此外，NP-C小鼠的ALLO治疗显著增加小脑浦肯野和颗粒细胞存活，并显著减少皮质神经节苷脂GM 1、GM 2和GM 3的积累。作为向FDA提交IND用于未来NP-C儿童临床试验的先决条件，我们建议在野生型和NP-C小鼠中建立ALLO的药代动力学和药效学，优化NP-C小鼠中的ALLO治疗，并生成动物毒理学安全性数据。神经活性类固醇在治疗退行性脑疾病中的用途以前没有描述过。我们相信，其他脑部疾病，包括但不限于先天性胆积症，也很可能受益于神经活性类固醇的类似治疗。因此，该提议针对用一类新的药物治疗广泛的疾病，其中NP-C作为模型疾病。

DESCRIPTION (provided by applicant): Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood-on set neurodegenerative disorder for which there is no treatment. It is a lysosomal lipid storage disease characterized by defective trafficking of intracellular cholesterol, and lysosomal accumulation of unesterified cholesterol, gangliosides, and other lipids. Neurosteroids, synthesized from cholesterol in the nervous system, affect growth and differentiation of neurons. Our recently published data show that post-embryonic neurosteroid synthesis is altered in a time- and region- specific fashion in the BALB/c NP-C mouse, and that neurons and glia expressing steroidogenic enzymes are lost in the NP-C mouse. In particular, the synthesis of the GABA-ergic neurosteroid allopregnanolone (ALLO) is substantially diminished at birth when the rodent brain is still undergoing maturation, and decreases further over time. We hypothesize that these alterations in neurosteroidogenesis may contribute to the clinical phenotype. Our data show that appropriately timed treatment of NP-C mice with ALLO increases the lifespan of NP-C mice and delays the onset of neurological impairments that are hallmarks of this disease in mice - tremor, ataxia, and hindlimb dysfunction. Furthermore, ALLO treatment of NP-C mice significantly increases cerebellar Purkinje and granule cell survival and substantially reduces accumulation of cortical gangliosides GM1, GM2 and GM3. As a prerequisite for submission of an IND to the FDA for future clinical trials in children with NP-C, we propose to establish the.pharmacokinetics and pharmacodynamics of ALLO in wild type and NP-C mice, optimize ALLO treatment in NP-C mice, and generate toxicology safety data in animals. The use of neuro-active steroids in the treatment of degenerative brain diseases has not been described previously. We believe it is very possible that other brain diseases, including, but not limited to congenital storage diseases, may benefit from similar treatments with neuro-active steroids. Thus this proposal is directed toward the treatment of a broad group of disorders with a novel class of drugs, with NP-C as the model disease.