Proteomic Biomarker Tests in Blood Samples from Children with Autism Spectrum Disorder (ASD)

Behavioral testing is the gold standard for diagnosing autism spectrum disorder (ASD). These tests, including ADOS and ADI-R, are subjective, require trained staff to administer, are time-consuming, and can only be administered at a later age. Blood-, urine- or stool-based diagnostic biomarker test for ASD would enable objective early diagnosis, potentially even before clinical symptoms are present, eliminate the need for trained staff and enable early intervention. Such a test would not only conserve money and time but would also provide clues to ASD pathogenesis.

To date, no definitive treatment exists for ASD. Most therapies are symptom-focused, generally focusing on behavioral, social and communication skills. Recent works have reported on promising outcomes of mesenchymal stem cell (MSC) treatment of children with ASD. MSCs are multipotent, non-hematopoietic, easily isolatable and expandable stem cells involved in tissue repair, immunomodulatory responses and neuromodulation. MSC treatment of children with ASD has reportedly led to improvements in speech, sociability, eye coordination, balance, cognition and overall well-being. At the base of this approach lies the known plasticity of the human brain and immune system in the early childhood years and the ability of MSCs to modulate atypical inflammatory and immune activities. Assessment of ASD biomarker profiles in children with ASD who have undergone one or more SCT sessions may shed light on the mechanism of action, assist in better defining ASD-specific diagnostic markers and monitor treatment outcomes.

Study Overview

• Status: Recruiting
• Conditions: Autistic Disorder
• Intervention / Treatment: Diagnostic test: Blood draw; Diagnostic test: Stool Sample Collection; Diagnostic test: Urine Sample Collection

Detailed Description

There is accumulating evidence that at least a subset of children diagnosed with ASD also have aberrant immune functions. This study will attempt to identify more specifically the nature of the potential immune abnormalities in children.

The study will follow a case-control design, involving the following cohorts:

1. young children (2-12 years) diagnosed with ASD
2. children (12-18 years) diagnosed with ASD
3. age- and sex-matched typically developing children
4. high-risk infants (10-19 months) with at least one sibling with diagnosed ASD
5. mothers of these high-risk infants
6. young children (2-12 years) diagnosed with ASD and scheduled to undergo stem cell transplantation therapy (SCT)

Parents will be asked to complete several questionnaires relating to demographic and anamnestic details and to the child's development.

• A single blood draw from all participants will be performed in the clinic.
• A stool sample will be collected from high-risk infants.

• A stool and urine sample will be collected at home from children due to undergo SCT. For children scheduled to undergo SCT, the blood, stool and urine samples must be collected before therapy.

  • Parents of high-risk infants will be contacted by phone or email when the child reaches diagnosable age (3.5 years) and again at the age of 6 years, to obtain an update on the child's ASD status. If the child has been diagnosed with ASD, an additional blood and stool sample may be collected.
  • Children who underwent SCT will be contacted 2±1 months and 6±1 months after the first treatment session, for collection of additional blood samples. Stool and urine samples will be collected at the 6±1 month post-treatment visit as well. Should the child undergo additional SCT within two years of the first treatment, additional blood, stool and urine samples may be collected. At each subsequent visit, a parent/legal guardian will be asked to complete several short questionnaires.

Adverse events to blood drawing will be reported to the Data Coordinating Center using the appropriate Case Report Form (CRF).

In cases of adverse effects (AE) related to the drawing of blood or performance of examination of patients in the course of standard examination procedures, the investigating team will proceed in accordance with local guidelines (to be inserted by the PI), reporting the incidents which occurred during the course of a clinical trial.

Clinical data will be collected by the investigator, or a person appointed and appropriately trained by the investigator, and shall be entered into standardized CRFs and shared online with the sponsor. Source data will be retained for all data entered in the CRFs. Progress reports and the Final Report at the conclusion of the trial will be submitted to the regulatory authority and the Ethics Committee, as required.

• Study Type: Observational
• Enrollment (Estimated): 900

Contacts and Locations

• Study Contact: Name: Benjamin Gesundheit, M.D.; Email: gesundheitmd@cell-el.com
• Study Contact Backup: Name: Leah Hochbaum; Email: leah@cell-el.com

Study Locations

• Israel
  • Jerusalem, Israel, 91031
    • Recruiting
    • Shaare Zedek Medical Center
    • Contact: Avraham Steinberg, MD; Email: avraham@steinberg.onmicrosoft.com
    • Contact: Avraham Steinberg, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 months to 12 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

1. Up to a total of 350 male and female children, aged 2-12 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00)
2. Up to a total of 350 male and female typically developing (TD) children aged 2-12 years with no signs of ASD or history of ASD in the immediate family who will serve as controls for the main subset of children with ASD
3. Up to 50 infants aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) (herein, high-risk infants)
4. Up to 50 mothers of the high-risk infants participating in the study
5. Up to 50 male and female children, aged 2-12 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) scheduled to undergo stem cell therapy (SCT)
6. Up to 50 male and female children, aged 12-18 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) scheduled to undergo SCT

Description

Inclusion Criteria:

1. Male and female children
2. Child aged 2-12 years with diagnosed ASD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV (299.00) or DSM-V (299.00) OR Child aged 2-18 years diagnosed ASD according to DSM-IV (299.00) or DSM-V (299.00) AND scheduled to undergo stem cell transplantation OR Child aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD according to (DSM)-IV (299.00) or DSM-V (299.00) (herein termed "high-risk infants") OR Mothers of recruited high-risk infants OR A typically developing child aged 2-12 years with no signs of ASD or history of ASD in the immediate family
3. Informed consent signed by the parent/legal guardian

Exclusion Criteria:

1. Child and/or mother completed treatment with systemic steroids or immune suppressants less than 4 weeks before the screening visit
2. Child and/or mother diagnosed with severe infectious diseases or sepsis over the last 6 months
3. Child with ASD treated for a severe convulsive disorder (intractable seizures)
4. Child and/or mother with hematological or malignant disorder
5. For children in the SCT cohort: No new planned immune-modulating treatment (other than SCT) for at least 6 months before or after planned stem cell transplantation date
6. If the PI suspects that the participant will not comply with study requirements, the participant may be excluded.

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Control Group of Young Children; 2-12 years old age & sex-matched controls - typically developing (TD) children	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture
Young Children-Autism Spectrum Disorder; 2-12 years old children diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00)	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture
Young Children-Autism Spectrum Disorder+SCT; 2-12 years old children diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) due to undergo stem cell transplantation therapy	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture; Diagnostic test: Stool Sample Collection; Subjects will be provided a dry, plastic, screw-top specimen container and will be asked to collect a stool sample at home.; Other Names: Stool Analysis; Diagnostic test: Urine Sample Collection; Subjects will be provided a dry, plastic, screw-top specimen container and will be asked to collect a urine sample at home.; Other Names: Urinalysis
High-risk infants; Infants aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture; Diagnostic test: Stool Sample Collection; Subjects will be provided a dry, plastic, screw-top specimen container and will be asked to collect a stool sample at home.; Other Names: Stool Analysis
Mothers of high-risk infants; Mothers of recruited infants aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture
Adolescent-Autism Spectrum Disorder+SCT; 12-18 years old children diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) due to undergo stem cell transplantation therapy	Diagnostic test: Blood draw; A blood sample (5 mL) will be collected.; Other Names: blood sample; venepuncture; Diagnostic test: Stool Sample Collection; Subjects will be provided a dry, plastic, screw-top specimen container and will be asked to collect a stool sample at home.; Other Names: Stool Analysis; Diagnostic test: Urine Sample Collection; Subjects will be provided a dry, plastic, screw-top specimen container and will be asked to collect a urine sample at home.; Other Names: Urinalysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of discriminating proteomic biomarker profile in blood of children with ASD vs. matched TD children	Finding a proteomic signature in children with ASD	One day
Identification of discriminating proteomic biomarker profiles in blood of high-risk infants, at recruitment vs. after diagnosis of ASD, if diagnosed	Finding a proteomic signature in infants at high-risk of ASD	Up to 5 years after initial blood draw
Comparison of blood biomarker profiles in ASD children before versus after SCT	Finding ASD-specific blood proteomic biomarkers that can be modified by SCT	Through study completion, up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ASD severity vs. blood biomarker levels	Correlative assessment of ASD severity vs. blood biomarker levels	Through study, up to 5 years, depending on cohort
Blood biomarker levels and SCT outcomes	Correlative assessment of blood biomarker levels and SCT outcomes	Through study completion, up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of ASD-specific proteomic biomarkers and/or microbiome profile in stool samples of children with ASD before vs. after SCT	Identification of an ASD-associated proteomic/microbiome signature that may be altered by SCT	Up to 6 months
Comparison of urine biomarker profiles in ASD children before versus after SCT	Finding ASD-specific urine proteomic biomarkers that can be modified by SCT	Up to 6 months
Identification of ASD-specific proteomic biomarker and microbiome signature in stool samples of high-risk infants before vs. after ASD diagnosis, if diagnosed	Finding proteomic biomarker or microbiome signature in stool samples of high-risk infants that changes after diagnosis of ASD	Through study completion, up to 5 years
Identification of discriminating proteomic profiles in blood of the mothers of high-risk infants	Finding a proteomic signature that can identify mothers at risk of having an ASD child	One day
Correlative assessment of proteomic biomarker expression in the high-risk infant and his/her mother	Comparison of blood proteomic signature of a mother of a high-risk infant vs. that of the high-risk infant	1 day

Collaborators and Investigators

• Sponsor: Benjamin Gesundheit
• Collaborators: Shaare Zedek Medical Center
• Investigators: Principal Investigator: Benjamin Gesundheit, MD, Cell El Ltd

Publications and helpful links

General Publications

• Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Prochazka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P. Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun. 2013 Aug;44:1-7. doi: 10.1016/j.jaut.2013.05.005. Epub 2013 Jul 15.
• Gesundheit B, Zisman PD, Hochbaum L, Posen Y, Steinberg A, Friedman G, Ravkin HD, Rubin E, Faktor O, Ellis R. Autism spectrum disorder diagnosis using a new panel of immune- and inflammatory-related serum biomarkers: A case-control multicenter study. Front Pediatr. 2023 Feb 21;11:967954. doi: 10.3389/fped.2023.967954. eCollection 2023.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2013
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: June 19, 2014
• First Submitted That Met QC Criteria: June 19, 2014
• First Posted (Estimated): June 20, 2014

Study Record Updates

• Last Update Posted (Actual): November 25, 2024
• Last Update Submitted That Met QC Criteria: November 21, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Inflammation; Autism; Risk Factors; Autoimmune Diseases; Autistic Disorder; Child Development Disorders; Pervasive
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Autistic Disorder
• Other Study ID Numbers: CellEL-920130030

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No