Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Long-term SMN- and Ncald-ASO Combinatorial Therapy in SMA Mice and NCALD-ASO Treatment in hiPSC-Derived Motor Neurons Show Protective Effects

Anixa Muiños-Bühl
ORCID logo ,
Karen K Ling
,
Roman Rombo
,
Eleonora Zilio
ORCID logo ,
Frank Rigo
,
C. Frank Bennett
,
Brunhilde Wirth
* ORCID logo
Version 1 : Received: 30 January 2023 / Approved: 2 February 2023 / Online: 2 February 2023 (07:54:05 CET)

A peer-reviewed article of this Preprint also exists.

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.

Keywords

Neuromuscular disorder; NCALD; SMA; SMN2; Antisense oligonucleotide; Genetic modifier; Therapy; hiPSCs

Subject

Medicine and Pharmacology, Pathology and Pathobiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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