Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

DESCRIPTION (provided by applicant): Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More thanhalf of all cancer patients develop cachexia and it is responsible for more than 40% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake resulting in increased body weight. Ghrelin also stimulates the release of growth hormone, resulting in increased muscle mass, and ghrelin is reported to have anti-inflammatory activity. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 11 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies proposed in this application address each of these issues, resulting in the development of a long-acting ghrelin derivative that could be dosed less frequently. Extend Biosciences has a proprietary carrier molecule that lengthens circulating half-life, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. We have previously shown that when our carrier is conjugated to ghrelin, we can extend the half-life 22-fold, which is a significant improvement over native ghrelin. Additionally, we have shown that in vitro, carrier-conjugated ghrelin has the same receptor binding affinity as unconjugated ghrelin. We have also demonstrated that the carrier molecule greatly improves the bioavailability of a small protein when administered subcutaneously. The studies proposed in this Phase I application will investigate the ability of our long-acting ghrelin to stimulate growth hormone release from pituitary cells and increase food intake and body weight in healthy rats. This will allow us to show the in vivo functionality of conjugated ghrelin. We will address the importance of acylation by testing a constitutively active form of conjugated ghrelin. We will then test the leading candidate from these studies in an established model of cancer-induced cachexia in rats. An additional exploratory aim is to test subcutaneous dosing of our long-acting ghrelin along with the traditional intravenous dosing. SBIR Phase II funding will focus on GLP production andadditional in vivo and toxicology studies needed to begin human trials. Once fully developed, our long-acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patient with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). This technology can improve half-life and bioavailability of other peptide therapeutics as well.PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Cancer is often coupled with a serious condition called cachexia or involuntary weight loss. Studies have shown that cancer patients, who have cachexia often respond poorly to chemotherapy, are at a greater risk of infection and have a reduced life expectancy. Currently there is no effective way to treat cachexia. The work described in this proposal will help develop treatments for cachexia based on a hormone made by the body that increases appetite andstimulates muscle growth. Relieving the symptoms of cachexia will significantly improve a cancer patient's quality of life and decrease the need for hospitalizations, resulting in reduced healthcare costs.