Treatment of childhood regresive autism with minocycline

自闭症是一种神经发育障碍，导致社会和语言发育异常，并与僵硬和重复的行为有关。虽然有强有力的证据表明遗传性，但涉及的基因尚未确定。自闭症谱系障碍的患病率可能高达1/166。单卵双胞胎的平均一致率为70%，表明环境因素在疾病中起作用。自闭症儿童的亚群似乎对感染、免疫接种和饮食因素异常敏感，但这些因素中没有一个与该疾病有因果关系。尽管如此，根据间接证据，自身免疫被认为发挥了作用。对于自闭症，没有基于证据的有效治疗（Folstein和Rosen-Sheidley，2001）。 有一个自闭症儿童的亚组，似乎发展了一段时间，然后失去技能，或倒退。Vargas及其同事在约翰霍普金斯大学的一项最新研究表明，自闭症的退行性亚型与慢性脑神经炎症有关，如小胶质细胞和星形胶质细胞的激活以及组织样本（脑库）和CSF中测定的炎性细胞因子和生长因子的异常产生所例示的。作者评论说，这些反应类似于在一些神经退行性疾病，如肌萎缩侧索硬化症，和？慢性小胶质细胞激活似乎是导致持续神经炎症反应的原因，该反应促进多种神经毒性介质的产生。慢性神经胶质激活可能是胎儿发育模式异常持续的结果。在这种情况下，神经胶质细胞活化可能在启动和维持病理中发挥作用。或者，神经胶质细胞活化可能只是对起始致病因素的继发反应，而不是损伤的直接效应物。由于神经胶质细胞活化需要促炎转录因子NF-κ B的核转位，并且由于具有良好CNS抑制率的NF-κ B抑制剂是可用的，因此可以探索神经炎症在引发和维持自闭症病症中的作用。 抗生素米诺环素是小胶质细胞活化的强效抑制剂，显然是通过阻断NF-κ B核转位（Si et al.，2004年）。米诺环素在肌萎缩侧索硬化（ALS）小鼠模型中具有神经保护作用（货车Den Bosch et al. 2002），而亨廷顿？s病（Chen，M.例如，2000），最近已被证明可以稳定亨廷顿病的病程。在2年的时间内，在人类中观察到的S疾病（Bonelli，R.M.例如，2004年）。 为了评估自闭症儿童获益的可能性，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-κ B的核转位来减少炎症的药物。米诺环素是食品和药物管理局（FDA）批准用于治疗各种感染，并已广泛用于治疗青少年痤疮。米诺环素目前正处于治疗亨廷顿？和肌萎缩侧索硬化症。 该提案是一项为期6个月的初始、单臂、标签外、开放标签研究（为应答者提供3个月的扩展期），将在10名年龄为3至12岁的儿童中评估米诺环素的剂量安全性和疗效，这些儿童的主要诊断为自闭症，有发育退化史。将通过诊断/行为评估对受试者进行评价，并通过6个月治疗前后的CSF细胞因子/趋化因子谱判断神经炎症程度。受试者还将每天两次给予0.6 mg/kg维生素B6，作为可能的米诺环素诱导的恶心和呕吐的预防剂。如果这项可行性研究的结果令人鼓舞，我们希望进行一项二甲胺四环素治疗的双盲、安慰剂对照试验。

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 Huntington?s disease (Chen, M. et al., 2000) and has been recently shown to stabilize the course of Huntington?s 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 Huntington?s 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.