Abstract Details

Title Proteomic Profiling of Angelman Syndrome for Disease-associated Biomarker Discovery

Topic Child Neurology and Developmental Neurology

Presentation(s) P8 - Poster Session 8 (5:30 PM-6:30 PM)

Poster/Presentation
Number 8-001

Objective To explore the feasibility of identifying Angelman syndrome (AS)-associated biomarkers in the cerebrospinal fluid (CSF) of patients with AS as part of a pre-competitive consortium funded by the Foundation for Angelman Syndrome Therapeutics.

Background AS is a rare neurodevelopmental disorder characterized by severe impairment of speech, cognition, and motor function, as well as epilepsy and sleep disorders. Biomarkers could reduce the complexity of therapeutic development for AS by: 1) providing a measurement of target coverage, 2) connecting clinical effects with changes in underlying disease biology, and 3) allowing the development of quantifiable molecular efficacy measures that complement novel AS-specific clinical outcome measures.

Design/Methods CSF samples were collected from patients with AS (N=29), neurotypical controls (NTC; N=22), and genetic disease controls (GDC; N=14) comprising Niemann Pick Type C (NPC; n=10) and Batten Disease (CLN2; n=4). Mean age (years) was 6.8 for patients with AS, 13.0 for NTC, 11.3 for NPC, and 8.0 for CLN2. Proteomic profiling was performed using the aptamer-based Somalogic SomaScan^® assay covering 7,000 proteins. Following quality control, a paired t-test statistical comparison was run between NTC/GDC and AS datasets. Intra-patient comparisons were also performed.

Results The criticality of controlling pre-analytical variables in the analysis of CSF was established following iterative QC. Three neuroligins (NLGN1, NLGN2, and NLGN3), highly expressed cell-surface molecules in central nervous system tissues that are involved in the regulation of synaptic function, were found to be increased ~2.5x in AS samples vs controls. Additional potential differentially detected molecules were identified by examination of both fold-change and statistical significance.

Conclusions NLGN1, NLGN2, and NLGN3 are potential AS-associated biomarkers, a finding that should be validated using an independent sample set and with quantifiable assays specific to NLGN1, NLGN2, and NLGN3. Further analyses are ongoing.

Authors/Disclosures
Rachael Hawtin (Ultragenyx Pharmaceutical) PRESENTER	No disclosure on file
Julien Couthouis (Ultragenyx)	No disclosure on file
Showkhin Khan (Ultragenyx)	No disclosure on file
Ying Wang (Ultragenyx)	No disclosure on file
Jennifer Panagoulias (Jennifer Panagoulias)	No disclosure on file
Larry Gold (SomaLogic)	No disclosure on file
Sean Daugherty (Ultragenyx Pharmaceutical)	No disclosure on file
Dariusz Kunecki (Rush University Medical Center)	No disclosure on file
Elizabeth M. Berry-Kravis, MD, PhD (Rush University Medical Center)	The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Zevra. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren.
Allyson Berent (FAST)	No disclosure on file

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