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While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and -independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Kr\u00fcppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of\n                    <jats:italic>Klf15<\/jats:italic>\n                    in muscle of presymptomatic SMA mice. Importantly, perinatal upregulation of\n                    <jats:italic>Klf15<\/jats:italic>\n                    via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimized\n                    <jats:italic>Klf15<\/jats:italic>\n                    cDNA under the muscle-specific Spc5-12 promoter (AAV8-\n                    <jats:italic>Klf15<\/jats:italic>\n                    ). Administration of AAV8-\n                    <jats:italic>Klf15<\/jats:italic>\n                    to severe Taiwanese\n                    <jats:italic>Smn<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ;\n                    <jats:italic>SMN2<\/jats:italic>\n                    or intermediate\n                    <jats:italic>Smn<\/jats:italic>\n                    <jats:sup>\n                      2\n                      <jats:italic>B<\/jats:italic>\n                      \/\u2212\n                    <\/jats:sup>\n                    SMA mice significantly increased\n                    <jats:italic>Klf15<\/jats:italic>\n                    expression in muscle. We also observed significant activity of the AAV8-\n                    <jats:italic>Klf15<\/jats:italic>\n                    vector in liver and heart. AAV8-mediated\n                    <jats:italic>Klf15<\/jats:italic>\n                    overexpression moderately improved survival in the\n                    <jats:italic>Smn<\/jats:italic>\n                    <jats:sup>\n                      2\n                      <jats:italic>B<\/jats:italic>\n                      \/\u2212\n                    <\/jats:sup>\n                    model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time- and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart, and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.\n                  <\/jats:p>","DOI":"10.1038\/s41434-020-0146-8","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T12:04:02Z","timestamp":1587384242000},"page":"505-515","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice"],"prefix":"10.1038","volume":"27","author":[{"given":"Nina","family":"Ahlskog","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Hayler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Kubinski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-9445","authenticated-orcid":false,"given":"Peter","family":"Claus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzan M.","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J. 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