National Inst of Health Study Regressive Autism : Treatment with Minocycline: An Anti-Inflammatory

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This may be old news to some of you folks....I just thought it was interesting.

We can't participate I have a teenager with regressive autism...the study is

only for 3 to 12yr olds. But I really thought it was interesting

Title: Treatment of Childhood Regressive Autism with Minocycline: An

Anti-Inflammatory Agent Active Within the CNS

Number: 07-M-0024

Summary: 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 s 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-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.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Active Accrual

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria: 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: - Known genetic defect (e.g. Fragile X,

Down Syndrome, Tuberous Sclerosis, etc.). - 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 (see section V.D.) 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.

Special Instructions: Currently Not Provided

Keywords:

Pervasive Developmental Disorder

Immunology

Microglia

NF-Kappa-B

Antibiotic

Recruitment Keyword(s):

None

Condition(s):

Autism

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

None

Supporting Site:

National Institute of Mental Health

Contact(s):

Patient Recruitment and Public Liaison Office

Building 61

10 Cloister Court

Bethesda, land 20892-4754

Toll Free: 1-800-411-1222

TTY: 301-594-9774 (local),1-866-411-1010 (toll free)

Fax: 301-480-9793

Electronic Mail:prpl@...

Citation(s):

Auld DS, Robitaille R. Glial cells and neurotransmission: an inclusive view

of synaptic function. Neuron. 2003 Oct 9;40(2):389-400. Review.

Aman MG, Singh NN, AW, Field CJ. The aberrant behavior checklist: a

behavior rating scale for the assessment of treatment effects. Am J Ment Defic.

1985 Mar;89(5):485-91.

Barger SW, Moerman AM, Mao X. Molecular mechanisms of cytokine-induced

neuroprotection: NFkappaB and neuroplasticity. Curr Pharm Des.

2005;11(8):985-98. Review.

If you have:

Questions about participating in a study, please contact the Patient

Recruitment and Public Liaison Office, CC.

Technical questions regarding the Clinical Center web site, please contact

the Department of Networks and Applications, CC.

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