A Phase II Trial of Levodopa in Angelman Syndrome

描述（由申请人提供）： 本研究将研究左旋多巴在改善Angelman综合征（AS）儿童神经发育和运动障碍方面的疗效，这是一种罕见的神经发育障碍，患病率约为1/10，000至1/20，000。 AS的特征是智力迟钝、言语受限、癫痫发作、异常运动如震颤和共济失调步态。 目前，没有治愈AS的方法，治疗主要是支持性的。 钙/钙调蛋白依赖性激酶2型（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，它表明，过度磷酸化的CaMKII可能是负责在AS中看到的一些神经功能缺损。 左旋多巴（LD）是一种前药，可将多巴胺“递送”到大脑。 它通常与卡比多巴（CD），一种外周脱羧酶抑制剂一起使用，以增加LD的生物利用度。 动物研究表明，LD可以逆转参与突触和神经元功能的一些酶的过度磷酸化，包括CaMKII。 最近的数据表明，给予野生型和AS小鼠的外源性LD降低了脑中CaMKII的磷酸化，并导致AS小鼠的运动学习和表现的改善。 因此，我们推测口服LD/CD可以改善AS儿童的神经发育和运动障碍。 口服LD/CD已用于至少12名15个月至21岁的AS儿童。 然而，迄今为止尚未进行对照研究来评估LD/CD在儿童或成人中的使用。 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II期随机双盲安慰剂对照试验。 本研究将通过家长支持小组和专业组织招募AS儿童。 将100名AS儿童随机平均分配至安慰剂组或LD/CD组，并观察治疗1年。 本研究中使用的结果指标包括Bayley婴幼儿发育量表、Vineland适应行为量表、学龄前语言量表、异常行为检查表以及改良版的统一帕金森病评定量表。 在II期试验第一年完成后，所有受试者都可以选择在开放标签研究中继续接受LD/CD治疗一年，以获得更大受试者队列的长期安全性和可能的疗效数据。

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.