Proteins are largely quite delicate structures dependent on being manufactured and correctly folded and localized inside a cell. Thus no-one tries to make recombinant proteins or deliver them as a therapy for the vast majority of proteins. The exceptions are those proteins robust enough to be secreted by a cell and circulate in blood and other fluids in the body. In that case one can develop means of manufacture and build a recombinant protein that can be injected as a basis for therapy, assuming that more of that protein is a desirable goal. So far as I am aware it is unusual to find a protein that can survive oral administration and the harsh environment of the gastrointestinal tract, and then enter circulation to produce the same beneficial effects that the natively manufactured protein is capable of achieving. An energetic portion of the research community is actively engaged in trying to find ways to enable proteins to survive oral administration.
A fair amount has been written on the topic of BPIFB4 and its effects on life span and cardiovascular disease in recent years. The longevity-associated variant of the protein both reduces inflammation and reduces the impact of aging on the ability of blood vessels to contract and dilate. Exploration continues to try to fully understand its effects on the complex regulation of the vascular system. While the longevity-associated variant of BPIFB4 was discovered in humans, researchers have demonstrated in a number of studies that it produces benefits in aged mice. Today’s open access paper on this topic is largely interesting because the authors used oral administration of a recombinant longevity-associated variant of BPIFB4. This is not the expected next step after earlier success in mice with BPIFB4 gene therapies, precisely because, as mentioned above, very few proteins can be delivered orally.
Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models.
Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied n = 5 ApoE-/- mice on standard diet (SD), n = 5 (VEH-HFD) and n = 6 (LAV-HFD) ApoE-/- mice fed high-fat diet without or with rhLAV-BPIFB4 protein. Primary pre-adipocyte cultures were established from epididymal WAT to evaluate CD45+CD38+ leukocyte infiltration, inflammatory profile of pre-adipocytes, and ex vivo effects of conditioned media on vessels.
Oral administration of rhLAV-BPIFB4 in ApoE-/- mice fed high-fat diet dampens atherosclerosis by preserving endothelial integrity and reducing ICAM+ and CD68+ cell infiltration. Despite unchanged adiposity, systemically rhLAV-BPIFB4 reduces pro-inflammatory cytokines (IL-1α/β, TNF-α, IL-6) while mildly increasing IL-10 levels. Supernatants from pre-adipocytes treated with rhLAV-BPIFB4 demonstrate similar anti-inflammatory cytokine profiles. Conditioned media from rhLAV-treated eWAT ex vivo restores endothelial function in dysfunctional arteries. Collectively our data show that targeting adipocyte-associated inflammation, LAV-BPIFB4 emerges as a promising therapeutic strategy to counteract endothelial dysfunction in obesity.
