{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:06:32Z","timestamp":1788955592311,"version":"build-2803163510"},"posted":{"date-parts":[[2026,7,3]]},"group-title":"Physiology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH"},{"name":"the Marriott Family Foundation"},{"name":"the Abby Mac Foundation"},{"name":"the Daniel Garland Fund"},{"DOI":"10.13039\/100002108","name":"Friedreich\u2019s Ataxia Research Alliance","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Foundation for Anesthesia Education and Research Mentored Research Training Grant"},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  A growing body of pre-clinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for rare and common diseases (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, \u201chypoxia-in-a-pill\u201d combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2\u03b1 inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis (2). Although this small-molecule regimen extended the lifespan of the\n                  <jats:italic>Ndufs4<\/jats:italic>\n                  KO mouse model of mitochondrial complex I deficiency and Leigh syndrome, its efficacy did not match chronic 11% FIO2. Here we optimize this regimen using GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, and show it rescues key neurodegenerative phenotypes in multiple models. When we initiate therapy in 50 day old\n                  <jats:italic>Ndufs4<\/jats:italic>\n                  KO mice with advanced disease, GBT601 monotherapy alleviated neurological disease phenotypes and extended median lifespan from 62 days to 105 days, while dual therapy with the GBT601\/PT2399 combination extended median lifespan to 158 days. When initiated after onset of advanced disease in a mouse model of Friedreich\u2019s ataxia, the combination halted further progression of motor phenotypes. In a mouse model of Parkinson\u2019s disease due to a-synuclein toxicity, initiating the GBT601\/PT2399 combination after onset of neurodegeneration attenuates brain hyperoxia and lipid peroxidation and reverses motor phenotypes. Importantly, the combination maintained body weight without inducing any signs of pulmonary hypertension. Our findings motivate further pre-clinical and clinical evaluation of our \u201chypoxia in a pill\u201d approach for diseases with high unmet need.\n                <\/jats:p>","DOI":"10.64898\/2026.06.30.734089","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:56:00Z","timestamp":1783090560000},"source":"Crossref","is-referenced-by-count":0,"title":["A second-generation \u201chypoxia in a pill\u201d rescues neurodegenerative phenotypes across distinct mouse models"],"prefix":"10.64898","author":[{"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Systems Biology and Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eizo","family":"Marutani","sequence":"additional","affiliation":[{"name":"Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Zazzeron","sequence":"additional","affiliation":[{"name":"Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Menard","sequence":"additional","affiliation":[{"name":"Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Volpicelli-Daley","sequence":"additional","affiliation":[{"name":"Killion Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumito","family":"Ichinose","sequence":"additional","affiliation":[{"name":"Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9924-642X","authenticated-orcid":false,"given":"Vamsi K.","family":"Mootha","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Systems Biology and Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090904100695000_2026.06.30.734089v2.1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adr4049"},{"key":"2026090904100695000_2026.06.30.734089v2.2","doi-asserted-by":"crossref","unstructured":"H. Wang et al., Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2alpha. J Clin Invest 134 (2024).","DOI":"10.1172\/JCI185569"},{"key":"2026090904100695000_2026.06.30.734089v2.3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.819250"},{"key":"2026090904100695000_2026.06.30.734089v2.4","first-page":"2603","article-title":"Lower mortality rates in those living at moderate altitude","volume":"8","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"2026090904100695000_2026.06.30.734089v2.5","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1001\/jamapsychiatry.2015.1852","article-title":"Association Between Alzheimer Dementia Mortality Rate and Altitude in California Counties","volume":"72","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"2026090904100695000_2026.06.30.734089v2.6","doi-asserted-by":"publisher","DOI":"10.1097\/01376517-199708000-00007"},{"key":"2026090904100695000_2026.06.30.734089v2.7","doi-asserted-by":"publisher","DOI":"10.1007\/BF01553705"},{"key":"2026090904100695000_2026.06.30.734089v2.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9642"},{"key":"2026090904100695000_2026.06.30.734089v2.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1621511114"},{"key":"2026090904100695000_2026.06.30.734089v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.07.006"},{"key":"2026090904100695000_2026.06.30.734089v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.12.010"},{"key":"2026090904100695000_2026.06.30.734089v2.12","doi-asserted-by":"publisher","DOI":"10.1096\/FJ.201802655RR"},{"key":"2026090904100695000_2026.06.30.734089v2.13","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.63.12.21"},{"key":"2026090904100695000_2026.06.30.734089v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.03.045"},{"key":"2026090904100695000_2026.06.30.734089v2.15","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1093\/hmg\/ddad091","article-title":"Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich\u2019s ataxia","volume":"32","year":"2023","journal-title":"Hum Mol Genet"},{"key":"2026090904100695000_2026.06.30.734089v2.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920935117"},{"key":"2026090904100695000_2026.06.30.734089v2.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002117"},{"key":"2026090904100695000_2026.06.30.734089v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/nature20173"},{"key":"2026090904100695000_2026.06.30.734089v2.19","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1007\/s12975-018-0656-5","article-title":"Low Oxygen Post Conditioning as an Efficient Non-pharmacological Strategy to Promote Motor Function After Stroke","volume":"10","year":"2019","journal-title":"Transl Stroke Res"},{"key":"2026090904100695000_2026.06.30.734089v2.20","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1177\/0271678X20924107","article-title":"Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke","volume":"40","year":"2020","journal-title":"J Cereb Blood Flow Metab"},{"key":"2026090904100695000_2026.06.30.734089v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-025-02010-4"},{"key":"2026090904100695000_2026.06.30.734089v2.22","doi-asserted-by":"publisher","DOI":"10.4187\/respcare.11928"},{"key":"2026090904100695000_2026.06.30.734089v2.23","doi-asserted-by":"crossref","unstructured":"A. Sydykov et al., Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders. Int J Environ Res Public Health 18 (2021).","DOI":"10.3390\/ijerph18041692"},{"key":"2026090904100695000_2026.06.30.734089v2.24","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.006977"},{"key":"2026090904100695000_2026.06.30.734089v2.25","doi-asserted-by":"crossref","first-page":"e042608","DOI":"10.1161\/JAHA.125.042608","article-title":"Prolonged Postnatal Hypoxia Impairs Lung Development and Causes Severe Pulmonary Hypertension in Mice","volume":"14","year":"2025","journal-title":"J Am Heart Assoc"},{"key":"2026090904100695000_2026.06.30.734089v2.26","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0491OC"},{"key":"2026090904100695000_2026.06.30.734089v2.27","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-010-9402-1"},{"key":"2026090904100695000_2026.06.30.734089v2.28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200315496"},{"key":"2026090904100695000_2026.06.30.734089v2.29","doi-asserted-by":"publisher","DOI":"10.1126\/science.110.2865.543"},{"key":"2026090904100695000_2026.06.30.734089v2.30","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14214"},{"key":"2026090904100695000_2026.06.30.734089v2.31","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.6b00491"},{"key":"2026090904100695000_2026.06.30.734089v2.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.01.029"},{"key":"2026090904100695000_2026.06.30.734089v2.33","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1021\/acsmedchemlett.5c00076","article-title":"Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor","volume":"16","year":"2025","journal-title":"ACS Med Chem Lett"},{"key":"2026090904100695000_2026.06.30.734089v2.34","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.70028"},{"key":"2026090904100695000_2026.06.30.734089v2.35","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1080\/14656566.2025.2489123","article-title":"Osivelotor for the treatment of sickle cell disease","volume":"26","year":"2025","journal-title":"Expert Opin Pharmacother"},{"key":"2026090904100695000_2026.06.30.734089v2.36","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/bjh.18771","article-title":"GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model","volume":"202","year":"2023","journal-title":"Br J Haematol"},{"key":"2026090904100695000_2026.06.30.734089v2.37","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/ana.26716","article-title":"Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum","volume":"94","year":"2023","journal-title":"Ann Neurol"},{"key":"2026090904100695000_2026.06.30.734089v2.38","doi-asserted-by":"crossref","first-page":"267","DOI":"10.2217\/nmt-2022-0011","article-title":"Friedreich ataxia: clinical features and new developments","volume":"12","year":"2022","journal-title":"Neurodegener Dis Manag"},{"key":"2026090904100695000_2026.06.30.734089v2.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2011.01.010"},{"key":"2026090904100695000_2026.06.30.734089v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-51892-7.00017-6"},{"key":"2026090904100695000_2026.06.30.734089v2.41","doi-asserted-by":"crossref","unstructured":"V. Chandran et al., Inducible and reversible phenotypes in a novel mouse model of Friedreich\u2019s Ataxia. Elife 6 (2017).","DOI":"10.7554\/eLife.30054"},{"key":"2026090904100695000_2026.06.30.734089v2.42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.007743"},{"key":"2026090904100695000_2026.06.30.734089v2.43","first-page":"435","article-title":"A simple quantitative bradykinesia test in MPTP-treated mice","volume":"50","year":"1985","journal-title":"Res Commun Chem Pathol Pharmacol"},{"key":"2026090904100695000_2026.06.30.734089v2.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002443107"},{"key":"2026090904100695000_2026.06.30.734089v2.45","doi-asserted-by":"publisher","DOI":"10.1126\/science.1189406"},{"key":"2026090904100695000_2026.06.30.734089v2.46","doi-asserted-by":"publisher","DOI":"10.1126\/science.1190371"},{"key":"2026090904100695000_2026.06.30.734089v2.47","doi-asserted-by":"crossref","first-page":"e240232","DOI":"10.57264\/cer-2024-0232","article-title":"Adherence, treatment utilization, clinical and economic outcomes of patients with sickle cell disease with recurrent vaso-occlusive crises treated with recently approved chronic therapies in the US","volume":"14","year":"2025","journal-title":"J Comp Eff Res"},{"key":"2026090904100695000_2026.06.30.734089v2.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.02.004"},{"key":"2026090904100695000_2026.06.30.734089v2.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006214107"},{"key":"2026090904100695000_2026.06.30.734089v2.50","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.143"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.30.734089","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:19Z","timestamp":1788952219000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.30.734089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2026.06.30.734089","relation":{},"subject":[],"published":{"date-parts":[[2026,7,3]]},"subtype":"preprint"}}