Minocycline to Treat Childhood Regressive Autism
Condition: Autism; Minocycline; Regressive Autism
MeSH terms: Autistic Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      There is a subgroup of children with autism that appears to develop typically for a period of
      time, and then loses social or language skills, or regresses. A recent study by Vargas and
      co-workers at Johns Hopkins has demonstrated that this regressive type of autism is
      associated with chronic brain inflammation as shown by an abnormal production of inflammatory
      cytokines among other abnormalities.

      This present study will test the effectiveness of minocycline, an antibiotic with
      anti-inflammatory properties, in treating regressive autism. Although behavioral therapies
      have improved some symptoms of autism, there are no medical treatments for the disorder, and
      many children have ongoing behavioral difficulties. A medicine with anti-inflammatory
      properties may be beneficial for children with regressive autism.

      This will be an open-label trial, meaning all children in this study will receive
      minocycline. They will also receive vitamin B6 to reduce the possible chance of side effects
      of the minocycline.

      Children ages 3 to 12 with regressive autism may be eligible for this study. The children
      will take minocycline and vitamin B6 daily for 6 months. Prior to starting the medication and
      vitamin B6, children will receive a comprehensive diagnostic assessment for autism as well as
      a physical examination, medical history, and laboratory tests. Children will then receive
      ongoing assessments to monitor their behavior, communication, language skills, and medical
      issues at 2 weeks, and at 1, 2, 4, 6, and 12 months. Children who respond to the treatment
      will receive an additional 3 months of minocycline and vitamin B6.
    

Detailed description: 
      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.

      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 CS. 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-kappa B,
      and since inhibitors of NF-kappa-B 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-kappa-B nuclear translocation. Minocycline is neuroprotective in mouse
      models of amyotrophic lateral sclerosis (ALS) and Huntington's disease and has been recently
      shown to stabilize the course of Huntington's disease in humans over a 2-year period.

      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-kappa-B. 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.
    

Intervention name(s): Minocycline
Intervention type(s): Drug
Intervention MeSH terms: Minocycline
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunology; Microglia; NF-Kappa-B; Antibiotic; Autism; Minocycline; Regressive Autism