{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:50:44Z","timestamp":1774860644071,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,26]]},"group-title":"Neuroscience","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NINDS","award":["1R21NS121858"],"award-info":[{"award-number":["1R21NS121858"]}]},{"name":"NIH\/NINDS","award":["1R61NS131704"],"award-info":[{"award-number":["1R61NS131704"]}]},{"name":"SSADH Association"},{"name":"Boston Children's Hospital Translational Research Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive metabolic disorder due to loss-of-function\n                  <jats:italic>ALDH5A1<\/jats:italic>\n                  mutations impairing the catabolism of \u03b3-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. In SSADHD, pathologic accumulation of GABA and its metabolic by-product \u03b3-hydroxybutyrate (GHB) corresponds to a clinical syndrome dominated by developmental delay and epilepsy in half of patients with risk of sudden death in adolescence and adulthood. Brain-wide\n                  <jats:italic>ALDH5A1<\/jats:italic>\n                  gene replacement for SSADHD is unavailable, and whether such treatment will reverse the SSADHD phenotype is unknown. We developed an inducible mouse SSADHD model,\n                  <jats:italic>\n                    Aldh5a1\n                    <jats:sup>lox-STOP<\/jats:sup>\n                  <\/jats:italic>\n                  , enabling Cre-dependent\n                  <jats:italic>Aldh5a1<\/jats:italic>\n                  restoration to evaluate gene therapy feasibility. In the absence of SSADH,\n                  <jats:italic>\n                    Aldh5a1\n                    <jats:sup>lox-STOP<\/jats:sup>\n                  <\/jats:italic>\n                  mice exhibit hyperactivity and excessive serum GHB levels, culminating in death by \u223cpostnatal day 22, recapitulating the severe SSADHD condition. Systemic delivery of a blood-brain barrier (BBB)-penetrating adeno-associated virus (AAV) carrying a\n                  <jats:italic>Cre<\/jats:italic>\n                  gene to\n                  <jats:italic>\n                    Aldh5a1\n                    <jats:sup>lox-STOP<\/jats:sup>\n                  <\/jats:italic>\n                  mice leads to brain-wide SSADH restoration, serum GHB level reduction, normalization of hyperactivity, and substantial increase in survival. As a step toward clinical translation, we further assessed an AAV encompassing a functional native promoter (FLnP) of\n                  <jats:italic>ALDH5A1<\/jats:italic>\n                  tethered to its human coding sequence, namely AAV-FLnP-hALDH5A1.\n                  <jats:italic>\n                    Aldh5a1\n                    <jats:sup>lox-STOP<\/jats:sup>\n                  <\/jats:italic>\n                  mice were effectively rescued when treated with AAV-FLnP-hALDH5A1 packaged in the blood-brain barrier (BBB)-penetrating capsid PHP.eB. These findings provide preclinical proof that SSADH gene replacement therapy is feasible and potentially effective.\n                <\/jats:p>","DOI":"10.64898\/2026.03.24.713250","type":"posted-content","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:10:34Z","timestamp":1774588234000},"source":"Crossref","is-referenced-by-count":0,"title":["Postnatal gene restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD) reveals phenotype reversibility"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4975-7330","authenticated-orcid":false,"given":"Henry H.C.","family":"Lee","sequence":"first","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"},{"name":"Rosamund Stone Zander Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrielle","family":"McGinty","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Liebhardt","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7768-8101","authenticated-orcid":false,"given":"Zihe","family":"Zhang","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1980-7133","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Welzel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine; Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7020-8347","authenticated-orcid":false,"given":"Sheryl Anne D.","family":"Vermudez","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0934-0808","authenticated-orcid":false,"given":"Erland","family":"Arning","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1798-2927","authenticated-orcid":false,"given":"Rui","family":"Lin","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-2708","authenticated-orcid":false,"given":"Didem","family":"Cakici","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2988-7701","authenticated-orcid":false,"given":"Timothy","family":"Yu","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6636-3897","authenticated-orcid":false,"given":"Clifford J.","family":"Woolf","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6373-1068","authenticated-orcid":false,"given":"Phillip L.","family":"Pearl","sequence":"additional","affiliation":[{"name":"Epilepsy & Clinical Neurophysiology, Department of Neurology, Boston Children\u2019s Hospital, Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0097-9012","authenticated-orcid":false,"given":"Guangping","family":"Gao","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, UMass Chen Medical School, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"},{"name":"Rosamund Stone Zander Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital; Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6495-5928","authenticated-orcid":false,"given":"Alexander","family":"Rotenberg","sequence":"additional","affiliation":[{"name":"F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children\u2019s Hospital; Boston, USA"},{"name":"Rosamund Stone Zander Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital; Boston, USA"},{"name":"Epilepsy & Clinical Neurophysiology, Department of Neurology, Boston Children\u2019s Hospital, Boston, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026033001001647000_2026.03.24.713250v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(83)90018-9"},{"key":"2026033001001647000_2026.03.24.713250v1.2","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-3-2-106"},{"key":"2026033001001647000_2026.03.24.713250v1.3","unstructured":"Pearl, P.L. , Wiwattanadittakul, N. , Roullet, J.B. , and Gibson, K.M. (1993). Succinic Semialdehyde Dehydrogenase Deficiency. In GeneReviews((R)), M.P. Adam , H.H. Ardinger , R.A. Pagon , S.E. Wallace , L.J.H. Bean , K. Stephens , and A. Amemiya , eds. (Seattle (WA))."},{"key":"2026033001001647000_2026.03.24.713250v1.4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010730"},{"key":"2026033001001647000_2026.03.24.713250v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12668"},{"key":"2026033001001647000_2026.03.24.713250v1.6","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-973527"},{"key":"2026033001001647000_2026.03.24.713250v1.7","doi-asserted-by":"publisher","DOI":"10.1542\/peds.99.4.567"},{"key":"2026033001001647000_2026.03.24.713250v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000059549.70717.80"},{"key":"2026033001001647000_2026.03.24.713250v1.9","doi-asserted-by":"publisher","DOI":"10.1177\/0883073820981262"},{"key":"2026033001001647000_2026.03.24.713250v1.10","doi-asserted-by":"publisher","DOI":"10.1177\/0883073821993000"},{"key":"2026033001001647000_2026.03.24.713250v1.11","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181b163a5"},{"key":"2026033001001647000_2026.03.24.713250v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2011.04.013"},{"key":"2026033001001647000_2026.03.24.713250v1.13","doi-asserted-by":"publisher","DOI":"10.1177\/0883073820987742"},{"key":"2026033001001647000_2026.03.24.713250v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20686"},{"key":"2026033001001647000_2026.03.24.713250v1.15","doi-asserted-by":"publisher","DOI":"10.1177\/08830738211012804"},{"key":"2026033001001647000_2026.03.24.713250v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-1149-1"},{"key":"2026033001001647000_2026.03.24.713250v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/BF01799261"},{"key":"2026033001001647000_2026.03.24.713250v1.18","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1583183"},{"key":"2026033001001647000_2026.03.24.713250v1.19","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000210"},{"key":"2026033001001647000_2026.03.24.713250v1.20","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2011_60"},{"key":"2026033001001647000_2026.03.24.713250v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-018-0153-8"},{"key":"2026033001001647000_2026.03.24.713250v1.22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052606"},{"key":"2026033001001647000_2026.03.24.713250v1.23","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020477"},{"key":"2026033001001647000_2026.03.24.713250v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1934"},{"key":"2026033001001647000_2026.03.24.713250v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81826-7"},{"key":"2026033001001647000_2026.03.24.713250v1.26","doi-asserted-by":"publisher","DOI":"10.1177\/0883073821993000"},{"key":"2026033001001647000_2026.03.24.713250v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.153"},{"key":"2026033001001647000_2026.03.24.713250v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/ng727"},{"key":"2026033001001647000_2026.03.24.713250v1.29","doi-asserted-by":"publisher","DOI":"10.1097\/J.PAIN.0000000000002680"},{"key":"2026033001001647000_2026.03.24.713250v1.30","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002680"},{"key":"2026033001001647000_2026.03.24.713250v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.02.002"},{"key":"2026033001001647000_2026.03.24.713250v1.32","doi-asserted-by":"publisher","DOI":"10.1080\/15216540500264588"},{"key":"2026033001001647000_2026.03.24.713250v1.33","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.302.1.180"},{"key":"2026033001001647000_2026.03.24.713250v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2007.11.015"},{"key":"2026033001001647000_2026.03.24.713250v1.35","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-016-9959-4"},{"key":"2026033001001647000_2026.03.24.713250v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12735"},{"key":"2026033001001647000_2026.03.24.713250v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.01.013"},{"key":"2026033001001647000_2026.03.24.713250v1.38","doi-asserted-by":"publisher","DOI":"10.1126\/science.adm8386"},{"key":"2026033001001647000_2026.03.24.713250v1.39","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13101624"},{"key":"2026033001001647000_2026.03.24.713250v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2024.108363"},{"key":"2026033001001647000_2026.03.24.713250v1.41","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12635"},{"key":"2026033001001647000_2026.03.24.713250v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.forsciint.2010.03.035"},{"key":"2026033001001647000_2026.03.24.713250v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00969-4"},{"key":"2026033001001647000_2026.03.24.713250v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-022-00938-7"},{"key":"2026033001001647000_2026.03.24.713250v1.45","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.200"},{"key":"2026033001001647000_2026.03.24.713250v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.1"},{"key":"2026033001001647000_2026.03.24.713250v1.47","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-8-112"},{"key":"2026033001001647000_2026.03.24.713250v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.01.011"},{"key":"2026033001001647000_2026.03.24.713250v1.49","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0b013e32833b3397"},{"key":"2026033001001647000_2026.03.24.713250v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/32.12.1645"},{"key":"2026033001001647000_2026.03.24.713250v1.51","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0653-x"},{"key":"2026033001001647000_2026.03.24.713250v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.036"},{"key":"2026033001001647000_2026.03.24.713250v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"2026033001001647000_2026.03.24.713250v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.05.002"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.24.713250","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:00:27Z","timestamp":1774857627000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.24.713250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":54,"URL":"https:\/\/doi.org\/10.64898\/2026.03.24.713250","relation":{},"subject":[],"published":{"date-parts":[[2026,3,26]]},"subtype":"preprint"}}