Abstract Details

Title CSF IL-8 as a potential marker for gene therapy outcomes in Spinal Muscular Atrophy

Topic Child Neurology and Developmental Neurology

Presentation(s) P17 - Poster Session 17 (11:45 AM-12:45 PM)

Poster/Presentation
Number 6-005

Objective Cerebrospinal fluid (CSF) biomarkers in Spinal Muscular Atrophy (SMA).

Background Gene therapies have changed SMA outlook, but long-term responses continue to vary between individuals. In this study, we leverage the need for repeated intrathecal nusinersen injections to measure serial neurofilament light chain (NfL) and other CSF proteins as biomarkers of treatment response.

Design/Methods

Ten newly diagnosed and three older SMA type 1 (two SMN2 copies) children receiving nusinersen therapy consecutively recruited between March 2017 and January 2020. Clinical measures including age (months), weight (kg), CHOP-INTEND scores and CMAP (right APB, ADM) peak amplitudes serially collected. Before each nusinersen injection 5 mL CSF collected into sterile polypropylene tubes, labeled, frozen and stored at -80 ^°C. CSF samples batch-transferred for analysis using ELISA (NfL) or Luminex 200 platform (sAPP a and b; fractalkine, IL-8, IP-10, MCP-1). CSF biomarker levels were first log₁₀ transformed due to non-normal distribution, and then Z-transformed using the whole groups distribution for comparison between different biomarkers variances. Analysis of long-term motor outcomes was performed using linear mixed modeling to account for intra-subject correlation between adjacent timepoints. To discover if serial CSF analyte levels temporally correlated with motor measures, time-varying CSF analyte levels and their interaction terms with time were added as fixed variables.

Results NfL levels were strongly influenced by age, and its levels first declined before rebounding in many children. Among the six other serially analyzed CSF proteins (median four samples per child), levels of IL-8 (F(1, 47)=12.903, p=0.001) and sAPPa (F(1,47)=5.194, p=0.028) correlated with motor function measured by CHOP-INTEND scores, and IL-8 levels also longitudinally correlated with CMAP_APB(p=0.064). Furthermore, baseline IL-8 levels associated with greater motor improvement in the younger group (p=0.002).

Conclusions

Because of the linkage between longitudinal IL-8 and motor functions, we propose one-time CSF IL-8 measurement to improve clinical outcome prediction in SMA gene therapy.

Authors/Disclosures
Sumit Verma, MD (Emory Children's Center) PRESENTER	Dr. Verma has nothing to disclose.
	No disclosure on file
	No disclosure on file
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	No disclosure on file
William T. Hu, MD, PhD, FAAN (Rutgers Biomedical and Health Sciences)	Dr. Hu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fujirebio. Dr. Hu has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Beckman Coulter. Dr. Hu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apellis Pharmaceuticals. The institution of Dr. Hu has received research support from NIA. The institution of Dr. Hu has received research support from TMCity Foundation. The institution of Dr. Hu has received research support from Atlanta Family Foundation. The institution of Dr. Hu has received research support from Fujirebio Diagnostics.

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