Muiños-Bühl, A.; Rombo, R.; Ling, K.K.; Zilio, E.; Rigo, F.; Bennett, C.F.; Wirth, B. Long-Term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects. Int. J. Mol. Sci.2023, 24, 4198.
Muiños-Bühl, A.; Rombo, R.; Ling, K.K.; Zilio, E.; Rigo, F.; Bennett, C.F.; Wirth, B. Long-Term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects. Int. J. Mol. Sci. 2023, 24, 4198.
Muiños-Bühl, A.; Rombo, R.; Ling, K.K.; Zilio, E.; Rigo, F.; Bennett, C.F.; Wirth, B. Long-Term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects. Int. J. Mol. Sci.2023, 24, 4198.
Muiños-Bühl, A.; Rombo, R.; Ling, K.K.; Zilio, E.; Rigo, F.; Bennett, C.F.; Wirth, B. Long-Term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects. Int. J. Mol. Sci. 2023, 24, 4198.
Abstract
Here we investigated the longer-term effect of Ncald-ASOs by additional i.c.v. bolus injection at PND28. Two weeks after injection of 500 µg Ncald-ASO in wild-type mice, NCALD was significantly reduced in brain and spinal cord and well tolerated. Next, we performed a double-blinded preclinical study combining low-dose SMN-ASO (PND1) with 2x i.c.v. Ncald-ASO or CTRL-ASO (100 µg at PND2, 500 µg at PND28). Ncald-ASO re-injection significantly ameliorated electrophysiological defects and NMJ denervation at 2 months. Moreover, we developed and identified a nontoxic and highly efficient human NCALD-ASO that significantly reduced NCALD in hiPSCs-derived MNs. This improved both neuronal activity and growth cone maturation of SMA MNs, emphasizing the additional protective effect of NCALD-ASO treatment.
Medicine and Pharmacology, Pathology and Pathobiology
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