Genomics and Systems Biology analysis reveals differences in early versus late intervention group SMA patients receiving Onasemnogene abeparvovec


Spinal Muscular Atrophy

Poster Number: 126


SUMIT VERMA MD, Swati Bhasin PhD, Beena Thomas PhD, Khanjan Gandhi MS, Manoj Bhasin PhD


1. Principal Investigator/ Associate Professor, 2. AFLAC Blood and Cancer Center, Emory University School of Medicine, 3. AFLAC Blood and Cancer Center, Emory University School of Medicine, 4. Winship Cancer Center, Emory University School of Medicine, 5. AFLAC Blood and Cancer Center, Children's Healthcare of Atlanta and Emory University

Background: Spinal Muscular Atrophy (SMA) patients receiving gene therapy have limited surrogate gene markers and associated signaling pathways which may determine therapeutic response. Objective: We enrolled four SMA subjects receiving Onasemnogene abeparvovec and performed genome-wide expression profiling on pre- and post-gene therapy samples. RNA sequencing (RNAseq) libraries were prepared from buffy coat samples. Transcriptome profiling was performed using paired end RNAseq measuring expression of ~15,000 transcripts. Sequencing data was analyzed using standard statistical algorithms after quality control filtering, alignment to a human genome, and normalization to identify pre- and post- therapy differentially expressed genes (absolute fold change >2 and p- value <.05) using linear statistical models. Pathways, and Systems Biology analyses was performed using Ingenuity Pathways Analysis tool (IPA, Qiagen). Study was approved by local Institutional Review Board. Results: Gene therapy was delivered to 2 infants at median age 3 months (Early intervention group) and remaining 2 children at median age 20 months (Late intervention group). Early versus late intervention group median characteristics values as follows: weight (early 5.47 kg, late 8.65 kg), CHOP-INTEND (early 49, late 39.5, max 64), motor ADM CMAP (early 4.35, late 0.65 mV). Transcriptome analysis identified 296 genes that significantly altered after early treatment. These genes signify upregulation in pathways related to cellular development and signaling (ERK/MAPK pathway and Embryonic stem cell pluripotency). Systems biology analysis identified activation of CDK19, CCND1, CEBPA and inhibition of GATA1-3, KLF2, IL10, HNF4A, RUNX1. Late intervention group exhibited 306 differentially expressed genes involved in upregulation of chronic inflammatory pathways (IL-8, ENOS, STAT3). Systems biology analysis identified activation of inflammatory regulators including TNF alpha, IL-6, IL-3, IL-2, IL1beta, S100A8, S100A9. . In addition, Huntington disease pathway which was significantly elevated in the late treatment group, was downregulated in the early treatment group. Conclusion: Preliminary findings provide insight into the molecular mechanisms underlying the beneficial effects of early intervention. These findings will be further validated on larger cohort of SMA patients.