Abstract Details

Title Three-Dimensional Stem Cell-derived Spinal Cord Model for Investigating Therapeutic Mechanisms of Risdiplam-like Compounds in Spinal Muscular Atrophy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 11-001

Objective

To investigate the therapeutic mechanisms of a Risdiplam-like compound in a three-dimensional stem cell-derived spinal cord model for Spinal Muscular Atrophy (SMA) and assess its efficacy in reversing the disease's pathological hallmarks.

Background

SMA is a severe neurological disorder resulting from early degeneration of lower motor neurons due to mutations in the SMN1 gene. Reliable human models are crucial for understanding and treating this condition.

Design/Methods We developed and phenotypically characterized human spinal cord organoids from induced pluripotent stem cells (iPSCs) of SMA type 1 subjects (n=3) and healthy controls (n=2). The organoids were treated with a Risdiplam-like compound targeted at restoring SMN protein levels. The treatment was administered bi-daily across the first 80 days of organoid development, mimicking the initial trimester post-conception. Analysis methods included bulk transcriptomics, single-cell RNAseq, multielectrode array analysis, and immunophenotypic characterization.

Results SMA samples in the organoid model displayed marked cellular and molecular developmental alterations in multiple cell populations, notably beyond motor neurons. The Risdiplam-like compound modified at least 15% of disease-affected genes and showcased excellent long-term in vitro tolerance. Furthermore, it restored the balance between full-length SMN2 and Δ7, and importantly, reversed pathological indicators in the SMA organoids.

Conclusions The SMA organoids present a reliable model for studying drug kinetics and therapeutic outcomes, emphasizing the early and pervasive developmental nature of SMA. The study spotlights the potential of Risdiplam-like therapies for comprehensive SMA treatment and highlights the need for a profound understanding of drug mechanisms. Our findings notably contribute to the optimization of Risdiplam therapy, offering avenues for complementary treatment strategies for SMA patients.

Authors/Disclosures
Edoardo G. Spinelli, MD PRESENTER	Dr. Spinelli has nothing to disclose.
Andrea D'Angelo	Andrea D'Angelo has nothing to disclose.
Francesca Beatrice	Francesca Beatrice has nothing to disclose.
Jessica Ongaro (Ospedale Policlinico di Milano)	No disclosure on file
Paola Rinchetti	No disclosure on file
Irene Faravelli, MD, PhD (Harvard University)	Dr. Faravelli has nothing to disclose.
Matteo Miotto	Matteo Miotto has nothing to disclose.
Simona Lodato	Simona Lodato has nothing to disclose.
Monica Nizzardo	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.
Stefania Corti, MD, PhD (Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico)	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.

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