Treatment of childhood regresive autism with minocycline.

自闭症是一种神经发育障碍，会导致社会和语言发展的异常，并与僵硬和重复的行为有关。尽管有强有力的证据表明存在遗传性，但相关基因尚未确定。自闭症谱系障碍的患病率可能高达166人中有1人。同卵双胞胎的平均符合率为70%，这表明环境因素在疾病中发挥了作用。自闭症儿童的亚群似乎对感染、免疫和饮食因素异常敏感，但这些因素都没有与疾病产生因果关系。然而，自身免疫被认为在间接证据的基础上发挥了作用。目前还没有针对自闭症的循证有效治疗方法(Folstein和Rosen-Sheidley，2001)。 有一群患有自闭症的儿童似乎通常会在一段时间内发展起来，然后失去技能，或退化。约翰霍普金斯大学的Vargas和他的同事最近的一项研究表明，自闭症的退行性亚型与慢性脑神经炎症有关，例如在组织样本(脑库)和脑脊液中检测到的小胶质细胞和星形胶质细胞的激活以及炎性细胞因子和生长因子的异常产生。作者指出，这些反应类似于一些神经退行性疾病，如肌萎缩侧索硬化症，慢性小胶质细胞激活似乎与持续的神经炎症反应有关，这种反应促进了多种神经毒性介质的产生。慢性神经胶质细胞激活可能是胎儿发育模式异常持续的结果。在这种情况下，神经胶质细胞的激活可能在启动和维持病理过程中发挥作用。或者，神经胶质细胞的激活可能只是启动原因因素(S)的次要反应，而不是损伤的直接影响因素。由于神经胶质细胞的激活需要促炎转录因子NF-kappaB的核移位，而且由于有良好的中枢神经系统外显性的NF-kB抑制剂可用，因此可以探讨神经炎症在启动和维持自闭症条件中的作用。 抗生素米诺环素是一种强大的小胶质细胞激活抑制剂，显然是通过阻断核因子-kB核转位(Si等人，2004年)。米诺环素在肌萎缩侧索硬化症(ALS)小鼠模型中具有神经保护作用(Van Den Bosch等人。2002年)和亨廷顿病(Chen，M.等人，2000年)，最近被证明在两年内稳定了人类亨廷顿病的病程(Bonelli，R.M.等人，2004年)。 为了评估在自闭症儿童中受益的可能性，我们建议对抗炎抗生素米诺环素进行一项开放标签试验，米诺环素是一种通过阻断促炎转录因子NF-kB的核转位来减轻炎症的药物。米诺环素是美国食品和药物管理局(FDA)批准用于治疗多种感染的药物，已被广泛用于青少年痤疮的治疗。米诺环素目前处于治疗亨廷顿病和肌萎缩侧索硬化症的第三阶段试验。 这项建议是一项最初为期6个月的单臂非标签开放研究(向应答者提供3个月的延伸期)，将评估米诺环素在10名儿童中的剂量安全性和有效性，这些儿童最初被诊断为自闭症，有发育退化史。受试者将在治疗前和治疗6个月后接受诊断/行为评估，并通过脑脊液细胞因子/趋化因子图谱判断神经炎症的程度。受试者还将每天两次服用0.6毫克/公斤的维生素B6，作为预防米诺环素可能导致的恶心和呕吐的药物。如果这项可行性研究的结果令人鼓舞，我们预计将进行米诺环素治疗的双盲、安慰剂对照试验。 该方案得到了NIH IRB的批准。目前有3名患者入选，并接受了为期一个月的研究药物。

Autism is a neurodevelopmental disorder that results in abnormalities of social and language development and is associated with rigid and repetitive behaviors. Although there is strong evidence of heritability, the involved genes have not been identified. The prevalence of autism spectrum disorders may be as common as 1 in 166. The average concordance rate in monozygotic twins is 70% suggesting that environmental factors play a role in the disease. Subgroups of autistic children seem unusually sensitive to infections, immunizations and dietary factors, but none of these factors has been causally identified with the disease. Nevertheless, autoimmunity has been considered to play a role on the basis of indirect evidence. There is no evidence-based efficacious treatment for autism (Folstein and Rosen-Sheidley, 2001). There is a subgroup of children with autism that appear to develop typically for a period of time, and then lose skills, or regress. A recent study by Vargas and co-workers at Johns Hopkins has demonstrated that the regressive subtype of autism is associated with chronic brain neuroinflammation as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokines and growth factors assayed in both tissue samples (brain banks) and CSF. The authors remarked that these responses were similar to those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and that chronic microglia activation appears to be responsible for a sustained neuroinflammatory response that facilitates the production of multiple neurotoxic mediators. Chronic neuroglial activation could be the result of an abnormal persistence of a fetal development pattern. In this scenario neuroglial activation could play a role in initiating and in maintaining the pathology. Alternatively, neuroglial activation may only be a secondary response to the initiating causal factor(s) and not a direct effector of injury. Since neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappaB, and since inhibitors of NF-kB with good CNS penetrance are available, the role of neuroinflammation in initiating and sustaining the autistic condition can be probed. The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently through blockade of NF-kB nuclear translocation (Si et al., 2004). Minocycline is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS) (Van Den Bosch et al. 2002) and Huntingtons disease (Chen, M. et al., 2000) and has been recently shown to stabilize the course of Huntingtons disease in humans over a 2-year period (Bonelli, R.M. et al., 2004). To evaluate the possibility of benefit in autistic children, we propose to conduct an open-label trial of the anti-inflammatory antibiotic minocycline, an agent that reduces inflammation by blocking the nuclear translocation of the proinflammatory transcription factor NF-kB. Minocycline is Food and Drug Administration (FDA)-approved for treatment of a variety of infections and has been widely used for the treatment of adolescent acne. Minocycline is currently in phase III trials for the treatment of Huntingtons disease and amyotrophic lateral sclerosis. This proposal is for an initial 6-month, single-arm, off label, open-label study (with a 3 month extension phase offered to responders) that will evaluate dose safety and efficacy of minocycline in 10 children, ages 3 to 12 years, with a primary diagnosis of autism and a history of developmental regression. The subjects will be evaluated by a diagnostic/behavioral assessment, and the extent of neuroinflammation judged by CSF cytokine/chemokine profiles before and after the 6-month treatment. Subjects will also be given 0.6 mg/kg vitamin B6 twice a day as a prophylactic for possible minocycline induced nausea and vomiting. If the results of this feasibility study are encouraging, we expect to conduct a double-blind, placebo-controlled trial of minocycline therapy. This protocol was approvd by the NIH IRB. Currently 3 patients are enrolled and have received the study drug for one month.