A Phase II Trial of Levodopa in Angelman Syndrome

描述(由申请人提供)： 这项研究将调查左旋多巴在改善Angelman综合征(AS)儿童神经发育和运动障碍方面的疗效。AS是一种罕见的神经发育障碍，发病率约为1/10,000至1/20,000人。AS的特征是智力迟缓、言语受限、癫痫发作、异常运动，如震颤和共济失调步态。目前，AS还没有治愈方法，治疗在很大程度上是支持性的。钙/钙调蛋白依赖性激酶2(CaMKII)是突触后神经元中的一种酶，参与记忆和学习的形成。最近的研究表明，CaMKII的过度磷酸化可能是AS的一些神经功能缺陷的原因。 左旋多巴(LD)是一种将多巴胺“输送”到大脑的前药。它通常与外周脱羧酶抑制剂卡比多巴(CD)一起服用，以提高LD的生物利用度。动物研究表明，LD可以逆转一些与突触和神经元功能有关的酶的过度磷酸化，包括CaMKII。最近的数据显示，给予野生型和AS小鼠外源性LD可降低大脑中CaMKII的磷酸化，并导致AS小鼠运动学习和表现的改善。因此，推测口服LD/CD可以改善AS儿童的神经发育和运动障碍。 至少有12名15个月至21岁的儿童使用过口服LD/CD。然而，到目前为止，还没有开展对照研究来评估儿童或成人使用LD/CD的情况。本研究的具体目的是在4岁至12岁的AS儿童中进行LD/CD的2期随机、双盲、安慰剂对照试验。 患有强直性脊柱炎的儿童将通过家长支持团体和专业组织被招募参加这项研究。100名儿童将被随机均分，接受安慰剂或LD/CD，并在治疗中观察一年。这项研究中将使用的结果衡量标准包括贝利婴幼儿发展量表、Vinland适应行为量表、学龄前语言量表、异常行为检查表以及统一帕金森病评定量表的修订版。在第二阶段试验的第一年结束后，所有受试者将被允许选择在开放标签研究中继续使用LD/CD多一年，以获得更长期的安全性，并可能在更大的受试者队列中获得疗效数据。

DESCRIPTION (provided by applicant): This study will investigate the efficacy of levodopa in improving the neurodevelopment and movement disorders in children with Angelman Syndrome (AS), a rare neurodevelopmental disorder with a prevalence of approximately 1 in 10,000 to 1 in 20,000 individuals. AS is characterized by mental retardation, limited speech, seizures, abnormal movements such as tremors, and ataxic gait. Currently, there is no cure for AS and treatment is largely supportive. Calcium/calmodulin-dependent kinase type 2 (CaMKII) is an enzyme in post-synaptic neurons that is involved in the formation of memory and learning. Recently, it was shown that excess phosphorylation of CaMKII may be responsible for some of the neurological deficits seen in AS. Levodopa (LD) is a prodrug that "delivers" dopamine to the brain. It is usually given with carbidopa (CD), a peripheral decarboxylase inhibitor, to increase the bioavailability of LD. Animal studies have suggested that LD can reverse the excess phosphorylation of some enzymes involved in synaptic and neuronal function, including CaMKII. More recent data have shown that exogenous LD given to both wild-type and AS mice reduces the phosphorylation of CaMKII in the brain and leads to improvements in the motor learning and performance of the AS mice. Therefore, it is hypothesized that oral LD/CD will lead to an improvement in the neurodevelopment and movement disorder in children with AS. Oral LD/CD has been used in at least 12 AS children between 15 months and 21 years old. However, no controlled studies have been carried out to date to evaluate use of LD/CD in children or adults. The specific aim of this study is to conduct a Phase 2 randomized double-blind placebo-controlled trial of LD/CD in AS children between 4 years and 12 years old. Children with AS will be recruited for this study through parent support groups and professional organizations. One hundred AS children will be randomized equally to receive either placebo or LD/CD and observed on therapy for one year. Outcome measures that will be used in this study include the Bayley Scales of Infant and Toddler Development, the Vineland Adaptive Behavior Scales, the Preschool Language Scale, the Aberrant Behavior Checklist, as well as a modified version of the Unified Parkinson Disease Rating Scale. Upon completion of the first year of the Phase 2 trial, all subjects will be offered the option of continuing on LD/CD for an additional year in an open-label study to obtain longer-term safety, and possibly efficacy data in a larger cohort of subjects.