Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy

Osman, Erkan Y.; Washington, Charles W.; Simon, Madeline; Megiddo, Dalia; Greif, Hagar; Lorson, Christian L.

doi:10.3233/jnd-170230

Cited by 16 publications

(16 citation statements)

References 51 publications

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“…This approach was very effective in a mouse model of SMA, and extended survival, improved weight gain and "time to right". Dr. Lorson also discussed combinatorial treatments for SMA, including SMN-dependent [15] and SMNindependent [16] approaches. Dr. Charlotte Sumner (Johns Hopkins University School of Medicine, USA) gave an overview of the genetics of SMA and the very promising therapeutics currently approved (Nusinersen/Spinraza) or in development (AVSX-101, scAAV9-SMN1).…”

Section: Session 1: Innovations In Neuromuscular Disease and Transformentioning

confidence: 99%

Report on the 4th Ottawa International Conference on Neuromuscular Disease and Biology – September 5–7, 2017, Ottawa, Canada1

Warman‐Chardon

Jasmin

Kothary

et al. 2018

JND

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Section: Session 1: Innovations In Neuromuscular Disease and Transformentioning

confidence: 99%

Report on the 4th Ottawa International Conference on Neuromuscular Disease and Biology – September 5–7, 2017, Ottawa, Canada1

Warman‐Chardon

Jasmin

Kothary

et al. 2018

JND

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“…The severity of SMA has so far indicated that there is a relatively short therapeutic window to achieve a maximal effect, however, adjunctive or combinatorial strategies may expand this window, thereby increasing the number and the types of patients that respond to drugs. (26)(27)(28)(29)(48)(49)(50)(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, treatment of a severe SMA mouse model with Azithromycin, an FDA approved readthrough drug, in combination with a sub-optimal ASO dose significantly improved disease phenotype over either treatment alone (29). An important pipeline for complementary therapeutic pathways revolves around the identification of potent disease modifiers.…”

Section: Introductionmentioning

confidence: 99%

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

Villalón

Kline

Smith

et al. 2019

Human Molecular Genetics

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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 scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. 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.

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“…Intracerebroventricular (ICV) injections were performed at P2 as previously described 81,82 . For motor function analysis, time to right (TTR) experiments were conducted as previously described 38,83 . TTR was measured every day from P7 through P17 on control and SMNΔ7 experimental animal cohorts.…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of SMN evolution in mouse models of SMA

Osman

Bolding

Villalón

et al. 2019

Sci Rep

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Spinal Muscular Atrophy (SMA) is a monogenic neurodegenerative disorder and the leading genetic cause of infantile mortality. While several functions have been ascribed to the SMN (survival motor neuron) protein, their specific contribution to the disease has yet to be fully elucidated. We hypothesized that some, but not all, SMN homologues would rescue the SMA phenotype in mouse models, thereby identifying disease-relevant domains. Using AAV9 to deliver Smn homologs to SMA mice, we identified a conservation threshold that marks the boundary at which homologs can rescue the SMA phenotype. Smn from Danio rerio and Xenopus laevis significantly prevent disease, whereas Smn from Drosophila melanogaster , Caenorhabditis elegans , and Schizosaccharomyces pombe was significantly less efficacious. This phenotypic rescue correlated with correction of RNA processing defects induced by SMN deficiency and neuromuscular junction pathology. Based upon the sequence conservation in the rescuing homologs, a minimal SMN construct was designed consisting of exons 2, 3, and 6, which showed a partial rescue of the SMA phenotype. While a significant extension in survival was observed, the absence of a complete rescue suggests that while the core conserved region is essential, additional sequences contribute to the overall ability of the SMN protein to rescue disease pathology.

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Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy

Cited by 16 publications

References 51 publications

Report on the 4th Ottawa International Conference on Neuromuscular Disease and Biology – September 5–7, 2017, Ottawa, Canada1

Report on the 4th Ottawa International Conference on Neuromuscular Disease and Biology – September 5–7, 2017, Ottawa, Canada1

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

Functional characterization of SMN evolution in mouse models of SMA

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