GM1 Ganglioside Effects on Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）是一种缓慢但持续进行的神经退行性疾病，导致临床症状随时间推移而恶化。目前还没有确定的药物可以明确减缓或阻止PD的进展，或基本上阻止PD患者不可避免的功能下降。因此，迫切需要能够改变临床进展、增强受损神经元的修复、补救现有的神经病理学缺陷、恢复或增强多巴胺（DA）系统的残余部分的功能和/或激活代偿机制的疾病改善药物。GM 1神经节苷脂可能是这样的治疗。体内外研究表明，GM 1可挽救受损的DA能神经元，刺激DA能神经元的存活和修复以及功能性DA能终末的发芽，增加纹状体中的DA水平，并上调残留神经元的DA合成能力。PD患者中GM 1的初步临床研究显示，短期使用GM 1的患者临床改善，使用GM 1 2 - 5年的患者症状进展最小，停止长期使用GM 1后症状恢复进展。 这项研究的具体目标是： 1)在一项随机双盲安慰剂对照临床试验中，评估GM 1的临床疗效以及临床改善与纹状体DA能神经支配完整性的体内定量（通过多巴胺转运蛋白位点的PET成像评估）之间的关系。工作假设：GM 1神经节苷脂治疗将导致与对受损但存活的DA神经元的影响相关的症状改善，这可能通过纹状体中功能性DA能终末的发芽来实现。 2)评估长期（2年）使用GM 1神经节苷脂可在多大程度上稳定PD患者的症状或减缓症状/疾病进展（使用临床评价和多巴胺转运蛋白PET成像作为替代指标）。工作假设：长期使用GM 1将稳定PD患者的症状或减缓症状的进展，这可能伴随着随着时间的推移纹状体DA终末的丢失减少。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a slowly but relentlessly progressive neurodegenerative disorder resulting in a time-dependent worsening of clinical symptoms. No drug has yet been identified that definitively slows or stops the progression of PD or substantially forestalls the inevitable functional decline in PD patients. Thus, disease modifying drugs that can modify clinical progression, enhance repair of damaged neurons, remediate existing neuropathological deficits, restore or enhance function of residual parts of the dopamine (DA) system and/or activate compensatory mechanisms are sorely needed. GM1 ganglioside may be such a treatment. In vitro and in vivo studies have shown GM1 to rescue damaged DA neurons, stimulate survival and repair of DAergic neuron and sprouting of functional DAergic terminals, increase DA levels in the striatum and upregulate DA synthetic capacity of residual neurons. Preliminary clinical studies of GM1 in PD patients have shown clinical improvements in patients with short-term use of GM1 and minimal symptom progression in patients with 2 to 5 years of GM1 use with resumed progression of symptoms following discontinuation of long-term GM1 use. The specific aims of this research are: 1) Assess the clinical efficacy of GM1 and the relationship between clinical improvement and in vivo quantitation of the integrity of the striatal DAergic innervation (assessed by PET imaging of the dopamine transporter site) in patients with typical mild/moderate PD in a randomized double blind placebo-controlled clinical trial. Working hypothesis: GM1 ganglioside treatment will result in symptomatic improvements related to effects on damaged but viable DA neurons and this may be accomplished through sprouting of functional DAergic terminals in the striatum. 2) Assess the extent to which long-term (2 years) use of GM1 ganglioside may stabilize symptoms or slow symptom/disease progression in PD patients (using clinical evaluations and PET imaging of the dopamine transporter as a surrogate measure). Working hypothesis: Long-term GM1 use will stabilize symptoms or slow the progression of symptoms in PD patients and this may be accompanied by reduced loss of striatal DA terminals over time.