Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

International audienceAbstract Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 ( SMN1 ) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila -based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an antibiotic, can be potentially repositioned for the SMA treatment

(BO)2 -Doped Tetrathia[7]helicene: A Configurationally Stable Blue Emitter

Helicenes combine two central themes in chemistry: extended pi-conjugation and chirality. Hetero-atom doping preserves both characteristics and allows modulation of the electronic structure of a helicene. Herein, we report the (BO)(2)-doped tetrathia[7]helicene 1, which was prepared from 2-methoxy-3,3 '-bithiophene in four steps. 1 is formally derived by substituting two (Mes)B-O moieties in place of (H)C=C(H) fragments in two benzene rings of the parent tetrathia[7]helicene. X-ray crystallography revealed a dihedral angle of 50.26(9)degrees between the two terminal thiophene rings. The (P)-/(M)-1 enantiomers were separated by chiral HPLC and are configurationally stable at room temperature. The experimentally determined enantiomerization barrier of 27.4 +/- 0.1 kcal mol(-1) is lower than that of tetrathia[7]helicene (39.4 +/- 0.1 kcal mol(-1)). The circular dichroism spectra of (P)- and (M)-1 show a perfect mirror-image relationship. 1 is a blue emitter (lambda(em)=411 nm) with a photoluminescence quantum efficiency of phi(PL)=6 % (cf. tetrathia[7]helicene: lambda(em)approximate to 405 nm, phi(PL)=5 %)

Polymorphic Genetic Markers of the GABA Catabolism Pathway in Alzheimer's Disease

The compilation of a list of genetic modifiers in Alzheimer's disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied