Pharmacokinetics, pharmacodynamics, and efficacy of a small-moleculeSMN2splicing modifier in mouse models of spinal muscular atrophy
| Autor: | Ellen Welch, Friedrich Metzger, Sergey Paushkin, Karen K. Y. Ling, Jana Narasimhan, Gary Mitchell Karp, Nikolai Naryshkin, Anna Mollin, Hasane Ratni, Janet Petruska, Zhihua Feng, Xin Zhao, Francesco Lotti, Shirley Yeh, Sarah Tisdale, Josephine Sheedy, Amal Dakka, Marla Weetall, Livio Pellizzoni, Karen S. Chen, Chien-Ping Ko |
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| Rok vydání: | 2016 |
| Předmět: |
Central Nervous System
0301 basic medicine Genetically modified mouse RNA Splicing animal diseases Transgene Mice Transgenic SMN1 Biology Piperazines Muscular Atrophy Spinal Small Molecule Libraries Mice 03 medical and health sciences Exon Genetics medicine Animals Humans Molecular Biology Genetics (clinical) Skin Dose-Response Relationship Drug Alternative splicing Exons Articles General Medicine Spinal muscular atrophy medicine.disease SMA Molecular biology nervous system diseases 3. Good health Survival of Motor Neuron 2 Protein Alternative Splicing Disease Models Animal 030104 developmental biology Isocoumarins nervous system RNA splicing Leukocytes Mononuclear Cancer research |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. |
| Databáze: | OpenAIRE |
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