{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:54:30Z","timestamp":1793066070424,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of survival of motor neuron (SMN) protein inducing progressive muscle weakness and atrophy due to motor neurons degeneration. Despite benefits of SMN restoration therapies in patients, motor defects are still persistent. We investigated the potential of BIO101, a new drug candidate promoting muscle growth by activating the protective arm of the renin\u2010angiotensin system through the MAS receptor, as monotherapy or in combination with the SMN\u2010based therapy ASO\u201010\u201027 (Nusinersen).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>BIO101 was administrated daily on severe or mild Taiwanese SMA mouse models or diluted in culture medium of SMA patient\u2010derived myoblasts. The BIO101 effects were evaluated on severe SMA mouse model in\u00a0vivo (growth, survival and motor function), ex\u00a0vivo (motor neuron, neuromuscular junction maturation, skeletal muscle phenotype) and on muscle SMN expression, while motor function effects were evaluated on mild SMA mouse model. The in\u00a0vitro effects on proliferation, differentiation, metabolism and SMN expression of SMA patient\u2010derived myoblasts were analysed. Effects of the combination of BIO101 with ASO\u201010\u201027 were evaluated on severe SMA mouse model, in\u00a0vivo and on tissular intracellular AKT signalling and SMN expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In severe SMA mice, BIO101 alone protected lateral motor neurons (+20%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), limited muscular atrophy (+30%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), accelerated maturation of muscular fibres (+70% for fast\u2010twitch muscles) and neuromuscular junctions (+50% of perforated clustering,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) with more prominent effects on fast\u2010twitch muscles. Those adaptations led to an improvement of muscular function, significant at 7, 9 and 10\u2009days post\u2010natal (+2\u2010fold for crossed squares and time of suspension,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), which was also observed in mild SMA mice at 8 and 9\u2009months of age (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Interestingly, BIO101 treatment also improved SMA patient\u2010derived myoblast differentiation (+20% myotube diameter and nuclei\/myotube,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and anaerobic performances (ECAR, + 10%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.05) without any impact on the proliferative state and aerobic capacities through MAS receptor activation. All BIO101 effects were independent of SMN protein expression. When combined with the ASO\u201010\u201027, BIO101 enhanced even more muscle resistance to fatigue (&gt;\u20093\u2010fold over 27\u2009days for time of suspension,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) when compared with severe SMA mice treated with ASO\u201010\u201027 alone, without effects on survival through the activation of AKT intracellular pathway and independently of SMN protein expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We showed that BIO101 constitutes an efficient SMN\u2010independent therapy to improve muscle performance in SMA, which could open new therapeutic avenues for patients in combination with SMN\u2010based therapies, or as monotherapy for less severe forms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70104","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T07:03:18Z","timestamp":1761202998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Drug Candidate BIO101 for Spinal Muscular Atrophy as Monotherapy or Combined With the Antisense Oligonucleotide ASO\u201010\u201027"],"prefix":"10.1002","volume":"16","author":[{"given":"Cynthia","family":"B\u00e9zier","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; INSERM UMR\u2010S1124  Paris Cedex 06 France"},{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Cottin","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvin\u00a0Nazari","family":"Hashemi","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirella","family":"El\u00a0Khoury","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; INSERM UMR\u2010S1124  Paris Cedex 06 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00e9","family":"Clerc","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; INSERM UMR\u2010S1124  Paris Cedex 06 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Balducci","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Sapaly","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; INSERM UMR\u2010S1124  Paris Cedex 06 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Weill","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; INSERM UMR\u2010S1124  Paris Cedex 06 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Lafont","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"},{"name":"Sorbonne Universit\u00e9 Institut de Biologie de Paris\u2010Seine (BIOSIPE) &amp; CNRS  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Veillet","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre\u00a0J.","family":"Dilda","sequence":"additional","affiliation":[{"name":"Biophytis Sorbonne Universit\u00e9  Paris Cedex 05 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Charbonnier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 &amp; 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