The Role of a Biomarker in the Double Blind Placebo - Controlled Study of CM-AT in Children with Autistic Disorder Ages 3-8

Background:

Autistic Disorder (AD) and Autism Spectrum Disorder (ASD) is a behavioral disorder with no known etiology. Although multiple theories exist with respect to the underlying etiology, including the role of epigenetics, it is thought that multiple subtypes may exist across the autism spectrum. In some patients with ASD, primary GI immuno-pathology may leads to secondary immune activation in the CNS that may contribute to the neurological features of autism, as well as a local inability for the gastrointestinal system to function properly thereby reducing function. This reduced function may also lead to various missing components of complete digestion, which may also affect the brain and brain function by limiting the pool of available amino acids. One such subtype has been thought to be related to the lack of protease enzymes associated with protein breakdown, and the resulting available amino acid pools from which to make novel proteins 

Objectives:

The primary objective of this study was to examine the role of the endogenous lack of protease enzyme on the treatment of children with specific enzyme replacement as determined by a measured biomarker in a multi-site double blind placebo controlled study of CM-AT.

Methods:

The  determination of the levels of fecal chymotrypsin (FCT)was undertaken in a double blind placebo controlled study of over 150 children, who met the DSM-IV criteria for ASD on the ADI-R, and who were also screened on the SCQ to differentiate spectrum from non-spectrum disorders. Multiple stool levels of FCT were taken throughout the trial both in CM-AT treated and placebo treated children. Those who tested positive were also administered a battery of cognitive, behavioral and physiological tests.

Results:

Greater than 50% of children who met the screening criteria for Autistic Disorder, also screened for abnormal FCT at baseline.  These results were correlated with the outcomes measures from baseline to termination across the cognitive, behavioral and physiological domains. Differences in the FCT levels at termination were examined between the CM-AT administered children and those administered placebo. 

Conclusions:

The presence of a specific biomarker in greater than 50% of the children who screened positive for Autistic disorder, holds significance with respect to the children who require specific enzyme replacement therapy. The potential for identifying a subtype within the autism spectrum holds promise for the understanding of the disease and potential treatments. The findings indicate that within the autism spectrum there exists a subtype of children that have an endogenous lack of chymotrypsin which cleaves only essential amino acids in the digestive process. The three major proteases include trypsin, elastase and chymotrypsin. This endogenous lack of chymotrypsin may leave the child with a dearth of essential amino acids, and an amino acid prioritization problem, and an inability to synthesize new proteins. This subtype has heretofore never been identified in multi-site
double blind  placebo controlled trials