Abstract Details

Title Stem Cell-Derived Spinal Cord Organoid Model: Temporal and Cell-Specific Analysis of Molecular Effects of a Risdiplam Analogue

Topic Child Neurology and Developmental Neurology

Presentation(s) N2 - Neuroscience in the Clinic: Regenerative Rehabilitation (4:35 PM-4:45 PM)

Poster/Presentation
Number 002

Objective To investigate the molecular and functional effects of a risdiplam-like compound (RIS-L) using a 3D human spinal cord organoid model derived from iPSCs of spinal muscular atrophy (SMA) type 1 patients and healthy controls, aiming to optimize treatment parameters and identify potential complementary targets.

Background SMA is a severe neurological disorder caused by SMN1 gene mutations, leading to motor neuron degeneration. Risdiplam, an approved therapy, increases SMN protein levels by modifying splicing. RIS-L, with improved pharmacological properties, mimics risdiplam's action, but its precise molecular effects remain unclear.

Design/Methods We generated and characterized spinal cord organoids (SCOs) from iPSCs of SMA type 1 patients and healthy controls. We optimized RIS-L dosage and treatment timing, studied its molecular and functional consequences, and explored potential complementary pharmacological targets. Analyses included bulk gene expression profiling and single-cell transcriptomics.

Results SCOs derived from SMA type 1 patients successfully modeled disease characteristics. Repeated treatment with 150 nM RIS-L every 2 days up to day 300 was well-tolerated, providing the best molecular risk/benefit ratio and promoting motor neuron differentiation. Treatment initiation at day 45 of organoid development, compared to day 30, resulted in broader gene modulation and enhanced motor neuron differentiation. Both time points increased full-length SMN isoform levels. Bulk analysis revealed modulation of specific gene sets towards control levels. Single-cell analysis uncovered early differentiation defects associated with basal activity and hyperexcitability in SMA organoids. Notably, our findings indicate that RIS-L treatment should not be initiated too early in spinal cord development for optimal effects.

Conclusions Stem cell-derived spinal cord organoids prove to be a valuable tool for studying SMA treatments in a human proxy model. This model offers a robust platform for identifying complementary pharmacological targets within an extended therapeutic window, potentially improving future treatment strategies for SMA.

Authors/Disclosures
Stefania Corti, MD, PhD (Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico) PRESENTER	Dr. Corti has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Corti has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Corti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta.
Andrea D'Angelo	Andrea D'Angelo has nothing to disclose.
Francesca Beatrice	Francesca Beatrice has nothing to disclose.
Chiara Cordiglieri, PhD	Dr. Cordiglieri has nothing to disclose.
Matteo Miotto	Matteo Miotto has nothing to disclose.
Simona Lodato	Simona Lodato has nothing to disclose.
Megi Meneri, MD, PhD	Dr. Meneri has nothing to disclose.
Delia Gagliardi, MD, PhD	Dr. Gagliardi has nothing to disclose.
Federica Rizzo, MD (University of Bari Aldo Moro)	No disclosure on file
Giacomo Comi	Giacomo Comi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Giacomo Comi has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis.
Linda Ottoboni	Linda Ottoboni has nothing to disclose.

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