SynTEF1 restores the functional disease phenotype of SCA27B in an hiPSC-derived neuronal disease model

Abstract Spinocerebellar Ataxia 27B (SCA27B), caused by a deep-intronic GAA•TTC repeat expansion in FGF14, has recently been identified as one of the most frequent genetic ataxias. Yet its underlying disease mechanism remains largely unknown, and disease-modifying treatments targeting upstream disease mechanisms are lacking. Here we hypothesized that (i) SCA27B is caused by transcriptional repression of FGF14, leading to reduced neuronal excitability and synaptic transmission strength; (ii) which can be restored by a synthetic elongation transcription factor (Syn-TEF1). We assessed FGF14 mRNA levels by qPCR, and neuronal function by whole-cell patch-clamp recordings in network and autaptic cultures of SCA27B patient iPSC-derived NGN2-neurons. Change in all read-outs was then assessed also upon Syn-TEF1 treatment. FGF14 mRNA levels were significantly reduced in both heterozygous and biallelic SCA27B patient-derived neurons. This was associated with decreased neuronal excitability and decreased peak current density of voltage-gated sodium channels. Moreover, SCA27B neurons showed reduced synaptic transmission with decreased excitatory postsynaptic current (EPSC) amplitudes. Treatment with SynTEF1 restored FGF14 mRNA levels, thereby restoring neuronal excitability and synaptic transmission. These insights into SCA27B pathophysiology and its amelioration by SynTEF1 open new translational avenues for the development of disease-modifying gene-targeted therapies for SCA27B. Graphical Abstract Competing Interest Statement MSy has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Insmed, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, Quince, and Solaxa, all unrelated to the present manuscript.