Minocycline to Treat Childhood Regressive Autism

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.

- INCLUSION CRITERIA:

The sample will be children with:

- Diagnosis of idiopathic autism and regression

- Age between 3 and 12 years

- Willingness to undergo lumbar puncture for evaluation of proinflammatory CSF
cytokines

- Stable behavioral plus or minus medication therapies.

EXCLUSION CRITERIA:

- Significant prematurity at birth (less than 32 weeks gestation); or birthweight
significantly below normal for gestational age (SGA--small for gestational age).

- Neurologic disorders including cerebral palsy, uncontrolled epilepsy, and
Landau-Kleffner syndrome.

- Evidence of renal insufficiency or hepatic disease (to reduce the incidence of
side-effects, since minocycline is excreted by the kidneys following hepatic
metabolism)

- Increased risk of developing lupus-like syndrome with minocycline administration
(positive anti-double stranded DNA or anti-nucleosome antibody tests at baseline, or
presence of a first degree relative with S.L.E.)

- Recent (less than two months prior to study entry) initiation of a behavioral therapy
program or new psychotropic medication trial.

- Subjects on one of the medications/supplements listed as those with possible
interactions or those on high dose B6 supplementation. For those families who are
interested in the study but are on any of these medications/supplements at the time
of intake, they will be instructed to wean the medication as appropriate (working
with the prescribing MD), and they will be enrolled after a 6-week wash-out period.