Oxygen nanobubbles for tissue hypoxia

Active: 2020.03.01 - 2021.08.31
UK SPINE Scientific Liaison: Monica Spisar

The cellular response to hypoxia is complex. Hypoxic-ischaemic conditions lead to post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK. While upregulation of HIF-1α is a key response to hypoxia, during the aging process it induces a deficit in mitochondrial biogenesis, impairing energy dependent cellular processes, including cell and tissue repair. The subsequent accumulation of ROS, oxidation of lipids and proteins, and mutations in mitochondrial DNA accelerate the aging process by inducing a deterioration of cellular energetics, the cellular redox state, calcium homeostasis, and cell signalling.

Attempts to address the dysregulated response to hypoxia by intervening in the pathways above, most notably with sirtuins, have yet to meet with clear clinical success. Inhibition of HIF-1α has been a therapeutic target in several diseases, but efforts to develop small molecule inhibitors have thus far been unsuccessful. An alternative approach is to address the fundamental biology at the top of the signalling cascade--tissue hypoxia.

Pilot data indicate that oxygen loaded nanobubbles are capable of relieving tissue hypoxia, representing a novel intervention with wide therapeutic potential. Complementing a separate experimental medicine study which will establish whether oxygen nanobubble intervention is effective in relieving tissue hypoxia, this research will investigate the impact of nanobubble delivery on the cellular response and will identify blood biomarkers associated with HIF-regulated pathways. Together, outcomes will inform the design of a future clinical trial for the use of oxygen nanobubbles to prevent age-related multimorbidities.

The specific work will involve two avenues. First, the hypoxic joint will serve as a model of aging and the effects of oxygen nanobubbles on osteoclasts, fibroblasts, T & B cells, and endothelial cells will be measured to delineate the response of human primary cells. Second, blood from the experimental medicine study will be interrogated to determine whether oral oxygen nanobubbles alter HIF biology and its downstream signalling pathways. Data generated will include evidence of HIF inhibition, evidence of an anti-inflammatory, anti-angiogenic or anti-resorptive effect, and / or effects on disease severity. This investigation has the potential to identify a systemic biomarker of altered HIF biology and, thus, provide a short-term biomarker of biological effect to de-risk future clinical efficacy studies.