Stefania Corti
Exploring the Effects of Risdiplam-like Compound on Spinal Muscular Atrophy Using a 3D Stem Cell-Derived Spinal Cord Model
Autori
- FRANCESCA BEATRICE (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION – PH STUDENT)
- ANDREA D’ANGELO (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION – PHD STUDENT)
- JESSICA ONGARO (FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO – BIOINFOMATICIAN)
- PAOLA RINCHETTI (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION – PHD)
- IRENE FARAVELLI (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION – NEUROLOGIST)
- MATTEO MIOTTO (HUMANITAS UNIVERSITY – BIOINFOMATICIAN)
- SIMONA LODATO (HUMANITAS UNIVERSITY – PHD)
- GIACOMO COMI (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION, FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO – NEUROLOGIST)
- LINDA OTTOBONI (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION – PHD)
- STEFANIA CORTI (UNIVERSITY OF MILAN, DEP. OF PATHOPHYSIOLOGY AND TRANSPLANTATION, FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO – NEUROLOGIST)
Presentatore
STEFANIA CORTI
Modalità
Poster Session
Abstract
“Objective: This study aims to explore the molecular and functional consequences of a molecule modified from Risdiplam on spinal cord organoids derived from stem cells of Spinal Muscular Atrophy (SMA) patients.
Background: SMA is a rare and very severe neurological condition caused by mutations in the SMN1 gene that determine reduction of the encoded protein and ultimately to motor neuron degeneration. Human models are vital for understanding the disease and to evaluate potential treatment.
Design/Methods: We created and analyzed spinal cord organoids from SMA type 1 patients (n=3) and healthy individuals (n=2) from pluripotent reprogrammed cells. Organoids were treated with the Risdiplam-like compound to increase SMN protein level. Longitudinal repeated treatment was started at different early developmental time points and tissue was analyzed at 80 days. Assessments included transcriptomics in bulk, at single-cell level, multielectrode array, and immunophenotyping.
Results: The SMA organoids showed significant developmental changes across various cell types, extending beyond motor neurons (MNs). The compound modulated around 15% of genes at the latest time point and was well-tolerated in vitro. It corrected SMN2 splicing, mitigated SMA-specific abnormalities and guaranteed an increase in MN number.
Conclusions: SMA organoids are promising for studying drug actions and effects, underlining SMA’s developmental aspect. The success of Risdiplam-like treatments in altering disease trajectories encourages further research on drug mechanisms to complement existing SMA therapies.”