2. Academic Validation
  3. HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity

HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity

  • Cell. 2025 Feb 12:S0092-8674(25)00098-4. doi: 10.1016/j.cell.2025.01.029.
Skyler Y Blume 1,  Ankur Garg 1,  Yolanda Martí-Mateos 1,  Ayush D Midha 1,  Brandon T L Chew 1,  Baiwei Lin 2,  Cecile Yu 2,  Ryan Dick 2,  Patrick S Lee 2,  Eva Situ 2,  Richa Sarwaikar 2,  Eric Green 2,  Vyas Ramanan 2,  Gijsbert Grotenbreg 2,  Maarten Hoek 2,  Christopher Sinz 2,  Isha H Jain 3
Affiliations

Affiliations

  • 1 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 Maze Therapeutics, 171 Oyster Point Blvd STE 300, South San Francisco, CA 94080, USA.
  • 3 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, 3181 Porter Dr, Palo Alto, CA 94304, USA. Electronic address: isha.jain@gladstone.ucsf.edu.
PMID: 39965572 DOI: 10.1016/j.cell.2025.01.029
Abstract

We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.

Keywords

Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy.

Figures
Products