Two recent mouse experiments reveal that an anti-inflammatory antibody medication may help to alleviate two unrelated illnesses: Preterm birth and fatty liver disease.
Numerous illnesses are impacted by inflammation, including autoimmune disorders, cardiovascular conditions, and lung conditions like asthma. Scientists in the lab of Professor Joe G.N. Garcia, the associate vice president for research at the University of Florida Health, have been developing the anti-inflammatory medication ALT-100 for the past 20 years.
The findings, published in Frontiers in Physiology and The FASEB Journal, say eNAMPT, or extracellular nicotinamide phosphoribosyltransferase, a protein essential for inflammation and the innate immune response, is the target of this medication. By attaching to the toll-like receptor 4 (TLR4) on innate immune cells, eNAMPT promotes inflammation. This starts an inflammatory cascade that prevents infections from spreading past a small geographic area. However, an overabundance of eNAMPT can harm organs, cause systemic inflammation, and accumulate in bodily tissues.
"The eNAMPT protein may be the most important factor in amplifying the innate immune response," says Garcia. "When eNAMPT regulation is impaired, the results are potentially disastrous."
The researchers examined whether ALT-100 may enhance outcomes from two unrelated inflammatory disorders – preterm birth associated with urinary infection and non-alcoholic fatty liver disease (NAFLD) connected to obesity – in two of the group's most recent pre-clinical investigations. In both cases, inflammatory signals increase dramatically, which worsens patient outcomes.
There are few effective treatments for preterm delivery. Antibiotics and anti-inflammatory drugs cannot postpone labor or stop harm to the unborn child from being caused by it, even though infection or inflammation may be the cause. The researchers' findings revealed greater eNAMPT levels in women whose pregnancies terminated early.
This was also seen in a mouse model of infection throughout late pregnancy. Preterm birth was caused by an overabundance of eNAMPT in the placenta and amniotic sac surrounding the fetus, which led to lower survival rates and severe impairments in the kids. Pregnant mice given ALT-100 treatment postponed miscarriage, and their offspring's impairment and mortality were decreased.
"Complications due to premature births, before 37 weeks gestation, are a leading cause of death worldwide among children under 5, resulting in approximately 900,000 deaths each year," says lead author Mohamed Ahmed. "This is a major unmet global medical need. Our results offer promise for this serious need."
The second research looked at the function of eNAMPT in NAFLD, a disorder linked to obesity that results in weakness, tiredness, stomach discomfort, and inflammation. Fat cells in the liver secrete excessive eNAMPT, leading to an unbalanced metabolism and a vicious cycle.
ALT-100 treatment reduced liver damage and fibrosis, or the accumulation of scar tissue in the liver, in NAFLD mouse models compared to untreated animals. Additionally, people with metabolic syndrome and type 2 diabetes frequently have higher-than-normal blood levels of eNAMPT. ALT-100 also decreased insulin resistance and glucose intolerance in the NAFLD mice models given a high-fat diet, lowering their risk of developing type 2 diabetes.
"Inflammation plays a serious role in the transition from fatty liver to liver fibrosis, cirrhosis and liver cancer. We believe that the production of eNAMPT contributes to this transition, with the ALT-100 monoclonal antibody a potential therapeutic to mitigate this in a precision medicine fashion."- Garcia
Garcia says preterm birth's sorrow and the complex, lengthy chain of illnesses it causes, including cirrhosis and liver cancer, raise the possibility that halting the inflammatory cascade might block the advancement of a wide variety of severe ailments for which few effective treatments exist.
Acute respiratory distress syndrome (ARDS), a severe condition of patients with respiratory failure needing mechanical ventilation, will shortly be tested in a clinical trial involving participants. According to scientists, ALT-100 may benefit autoimmune conditions, including lupus and inflammatory bowel illness as well.
Garcia concludes: "I believe that our antibody is a highly novel and potentially impactful tool to address multiple serious unmet needs around the world. It will be gratifying to validate this hope in our upcoming clinical trials."
- The FASEB Journal. Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis.
- Frontiers in Physiology. The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes.
- National Center for Biotechnology Information. How does the immune system work?
- Aqualung Therapeutics, corp. ALT-100 What is the protein eNAMPT?