This is an orthologue of the stasimon/tmem41b gene, a downstream target of SMN, the depleted protein in spinal muscular atrophy (SMA), which partially recapitulates the SMA phenotype in fly and zebrafish models when mutated.
The combined treatment of SMA cells with sub-optimal doses of LBH589 and of an antisense oligonucleotide that mimic Nusinersen (ASO_ISSN1) elicits additive effects on SMN2 splicing and SMN protein expression.
Recently, these features were harnessed in a clinical trial conducted by AveXis in SMA patients, where AAV9 was employed as a vehicle for one-time administration of the SMN gene, the causative gene in SMA.
Lentiviral-mediated transgenic expression of SMN where the dilysine domain in exon 2b was mutated was not able to rescue the SMA phenotype despite robust expression of the mutant SMN protein in brain, muscle and spinal cord.
We report here the finding of abnormal Golgi apparatus morphology in motor neuron like cells depleted of SMN as well as Golgi apparatus morphology in SMA patient fibroblasts.
The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating <i>SMN2</i> levels.
Then, to implement the fetal gene therapy, mouse fetuses received a single i.c.v. injection of a single-stranded (ss) or self-complementary (sc) AAV9-SMN vector that led to a lifespan of 93 (median of 63) or 171 (median 105) days for SMA mice.
Primary hits were further evaluated for their ability to correct the splicing defect and resultant increase of SMN activity in SMA patient-derived fibroblasts.
SYNCRIP overexpression rescued spinal muscular atrophy motor neurons, due to the subsequent increase in SMN and their downstream target NRXN2 through a positive loop mechanism and ameliorated SMN-loss-related pathological phenotypes in Caenorhabditis elegans and mouse models.
Onasemnogene abeparvovec (onasemnogene abeparvovec-xioi; formerly AVXS-101; ZOLGENSMA<sup>®</sup>) is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the human survival motor neuron (SMN) gene to the motor neuron cells of patients with spinal muscular atrophy (SMA).
<b>Background:</b> 5q spinal muscular atrophy (SMA) is an autosomal recessive lower motoneuron disease caused by deletion or mutations in the survival motor neuron 1 gene (<i>SMN1</i>) which results in reduced expression of full-length SMN protein.
Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain.ANN NEUROL 2019;86:458-462.
Recently, nusinersen, an antisense oligonucleotide (ASO) that corrects SMN2 splicing and thereby increases full-length SMN protein, has been approved by the FDA and EMA for SMA therapy.
Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.
In this study, a novel compound was identified that increased SMN protein levels in vivo and ameliorated the disease phenotype in severe and intermediate mouse models of SMA.
In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit.
Although it is well established that deficient expression of survival motor neuron (SMN) protein causes SMA, the molecular pathways that execute MN cell death are poorly defined.