AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy.

Human Molecular Genetics
E VillalónChristian L Lorson

Abstract

Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that s...Continue Reading

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Citations

Feb 1, 2020·Annual Review of Genomics and Human Genetics·Brunhilde WirthNatalia Mendoza-Ferreira
Sep 6, 2019·Nature Reviews. Neurology·Sarah Lemprière
Jan 8, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Natalia N SinghRavindra N Singh
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May 18, 2021·Frontiers in Molecular Biosciences·Olga KhorkovaClaes Wahlestedt

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