{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T05:47:40Z","timestamp":1793598460451,"version":"4.5.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012423","name":"Children\u2019s Healthcare of Atlanta","doi-asserted-by":"publisher","award":["1998 Society"],"award-info":[{"award-number":["1998 Society"]}],"id":[{"id":"10.13039\/100012423","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,30]]},"abstract":"<jats:p>\n                    Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder primarily affecting motor neurons, but immune dysfunction may contribute to disease progression and treatment response. While AAV9-delivered\n                    <jats:italic toggle=\"yes\">SMN1<\/jats:italic>\n                    gene therapy (e.g., Zolgensma) improves survival, long-term motor outcomes remain variable. This study integrates bulk and single-cell RNA sequencing (scRNA-seq) to define immune dysregulation in SMA. We analyzed peripheral blood from infants with SMA (n = 7 for bulk RNA-seq; n = 4 for scRNA-seq, &lt;25 mo of age) along with age-matched healthy controls (n = 4 for bulk RNA-seq; n = 6 for scRNA-seq). We profiled differentially expressed genes, immune pathways, cell\u2013cell interactions, and gene regulatory networks. SMA samples showed distinct transcriptomic signatures and elevated immune activation compared to controls.\n                    <jats:italic toggle=\"yes\">NECTIN1<\/jats:italic>\n                    was identified as a transcriptomic biomarker of disease progression, while\n                    <jats:italic toggle=\"yes\">HSPA7<\/jats:italic>\n                    was validated from prior reports. A 6- to 7-mo inflection point marked a transition from metabolic regulation to immune activation in SMA infants. NF-\u03baB\u2013related inflammatory gene expression was significantly elevated post\u2013gene therapy relative to both pretreatment and healthy controls, with\n                    <jats:italic toggle=\"yes\">IL1B<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">RNF19B<\/jats:italic>\n                    emerging as key transcriptomic mediators. scRNA-seq revealed early dysfunction and G1-phase arrest in CD4+ T-cells, along with a switch to\n                    <jats:italic toggle=\"yes\">RELB<\/jats:italic>\n                    -mediated noncanonical NF-\u03baB signaling. In symptomatic infants, CD8+ T-cells showed higher proliferation and exhaustion, with co-upregulation of\n                    <jats:italic toggle=\"yes\">TBX21<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">EOMES<\/jats:italic>\n                    , genes consistent with chronic stimulation and a trajectory toward terminal differentiation. Immune dysregulation is a central feature of SMA and may influence treatment response. These findings support future development of adjunct immunomodulatory strategies to enhance gene therapy efficacy and suggest that immune signatures may correlate with motor function outcomes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2506976122","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T15:49:17Z","timestamp":1758642557000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Biomarkers of immune dysregulation and posttreatment inflammation in spinal muscular atrophy"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2639-6269","authenticated-orcid":false,"given":"Sean C.","family":"Jordan","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT, Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta","place":["Atlanta"]},{"name":"Department of Biomedical Informatics, Emory University","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6733-0070","authenticated-orcid":false,"given":"Mojtaba","family":"Bakhtiari","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT, Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta","place":["Atlanta"]},{"name":"Department of Pediatrics, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati S.","family":"Bhasin","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT, Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta","place":["Atlanta"]},{"name":"Department of Pediatrics, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-420X","authenticated-orcid":false,"given":"Manoj K.","family":"Bhasin","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology\/BMT, Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta","place":["Atlanta"]},{"name":"Department of Biomedical Informatics, Emory University","place":["Atlanta"]},{"name":"Department of Pediatrics, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32003"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/joa.12083"},{"key":"e_1_3_4_3_2","first-page":"801","article-title":"Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice","volume":"26","author":"Deguise M. 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