Endocrine Abstracts

Background: Parathyroid hormone (PTH) is a peptide hormone consisting of 84 amino acids with residues 1–34 responsible for its biological activity. Hypoparathyroidism is a rare, complex condition with a patient predisposition toward impaired mineral homeostasis. Replacement with Natpara (PTH 1-84) requires daily injections and is still complicated by fluctuating calcium levels. An unmet need exists for a long-acting treatment that is effective. It is hypothesised that a P...

Rationale: Over the last 20 years, granulocyte colony-stimulating factor (GCSF) has become a recognized therapy in the treatment of patients suffering from neutropenia. Current therapies require daily injections of GCSF to stimulate stem cell production and response to treatment is often unpredictable as GCSF is rapidly cleared. A number of approaches to reducing GCSF clearance have been tried mainly through conjugation with another moiety. The technologies already being emplo...

Hypoparathyroidism causes severe hypocalcaemia and defective skeletal metabolism. Treatment with calcium and vitamin D supplementation can cause kidney failure whilst native parathyroid hormone (PTH) requires repeated injections and causes renal impairment paralleling high peak and low trough PTH levels. A long-acting PTH, providing constant physiological levels, is needed. LA-PTH, a hybrid of PTH and PTH related peptide, prolongs cAMP responses via altered receptor mechanisms...

Introduction: Leptin is a 16-kDa peptide hormone secreted by adipose tissue and acts as a sensor for energy stores. It feedsback at the hypothalamic arcuate nucleus to suppress appetite. Leptin treatment has been highly effective in suppressing appetite in the rare cases of leptin-deficient obesity and improving the metabolic profile in congenital generalised lipodystrophy. These patients require 2.5–10 mg once daily recombinant leptin treatment. We hypothesised that prol...

Background: The UK acromegaly register reported that <60% of acromegalics on medical therapy had controlled disease (1). Pegvisomant, a growth hormone antagonist (GHA), controls disease in >95% cases, but is not cost-effective and requires high dose daily injections (2). We have developed a fusion technology for making a cost-effective long-acting GH molecule (3), and generated a GHA by linking mutated growth hormone to its binding protein (GHBP).<p class="abstext"...

Background: The UK acromegaly register reported that <60% of acromegalics on medical therapy had controlled disease (1). This is because many patients do not respond to somatostatin therapy. Pegvisomant, a growth hormone antagonist (GHA), controls disease in >95% cases, but is not cost-effective and requires high dose daily injections (2). There is therefore an unmet need for a cost-effective GHA. We have developed a fusion technology for making a cost-effective long-a...

Background: Acromegaly is associated with increased morbidity and mortality, however currect medical treatment controls the disease in <60% of patients. Pegvisomant, a pegylated GH antagonist, controls the disease in over 95% of cases, but is not cost effective as it requires high dose daily injections and has side-effects. We have developed a technology for generating a long acting potent GH antagonist.Hypothesis: That a GH antagonist fused to GH bi...

Introduction: Glycosylphosphatidylinositol (GPI) anchored proteins are common on the surfaces of eukaryotic cells. An example is alkaline phosphatase. Fluorescently Labelled Aerolysin (FLAER) is a bacterial toxin produced by the gram-negative bacterium Aeromonas hydrophila that binds naturally to GPI anchored proteins and utilizes them as receptors to cause cytotoxicity. FLAER has been used to discriminate the GPI deficient red blood cells in cases of paroxysmal nocturn...

Background: The development of recombinant biologics has had a major impact on many diseases. However, most biologics are rapidly cleared from the body and therefore require frequent injection regimens. There is therefore a need for technologies that allow the half-lives of these molecules to be extended in a predictable manner.HypothesisIncreasing numbers of N-linked glycosylation motifs between two GH molecules leads to gradually...

Background: The development of recombinant biologics such as interferon, insulin and Growth Hormone (GH) has had a major impact on the management of diseases including hepatitis, diabetes and GH-deficiency. However, most biologics undergo rapid renal filtration and proteolytic degradation, necessitating frequent dosing regimens. Pegylation can successfully delay clearance but has several drawbacks including potential toxicity, expense and reduced activity. There is therefore n...