Neurosteroids in health and disease

描述(由申请人提供)： 尼曼-皮克C型(NP-C)病是一种致命的常染色体隐性遗传的儿童期神经退行性疾病，目前尚无治疗方法。它是一种溶酶体脂肪储存疾病，其特征是细胞内胆固醇运输缺陷，以及未酯化胆固醇、神经节苷脂和其他脂类的溶酶体积聚。神经类固醇是由神经系统中的胆固醇合成的，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有的方式改变，并且在NP-C小鼠中表达类固醇生成酶的神经元和胶质细胞丢失。特别是，当啮齿类动物的大脑仍处于成熟阶段时，GABA能神经类固醇别孕酮(Allo)的合成在出生时就大大减少，并随着时间的推移进一步减少。我们推测，神经类固醇合成的这些改变可能与临床表型有关。我们的数据显示，适当时机使用Allo治疗NP-C小鼠可以延长NP-C小鼠的寿命，并推迟这种疾病的特征神经损伤的发生-震颤、共济失调和后肢功能障碍。此外，对NP-C小鼠的ALLO治疗显著提高了小脑浦肯野和颗粒细胞的存活率，并显著减少了皮质神经节苷脂GM1、GM2和GM3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，我们建议建立Allo在野生型和NP-C小鼠中的药代动力学和药效学，优化在NP-C小鼠中的Allo治疗，并产生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使用在以前还没有被描述过。我们认为，其他大脑疾病，包括但不限于先天性储存疾病，很有可能从神经活性类固醇的类似治疗中受益。因此，这项建议旨在用一类新的药物治疗广泛的疾病组，以NP-C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.