Advancing peptide and proteins formulation to improve local delivery of macromolecules within the GI tract.

AIM: Oral local delivery of proteins to treat diseases in the gastrointestinal tract.
BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with an impaired immune response with periods of activity and remission. It is a lifelong, often debilitating condition, with no cure, which affects people of all ages. Along with ulcerative colitis (UC), CD is characterised by patchy cutaneous lesions (ulcers, fissures and abscesses), which can affect the entire stretch of the GI tract from mouth to anus. It typically presents with abdominal pain, fever, diarrhoea, weight loss and vomiting, with associated anxiety and depression. The development of the disease is unknown, but it is thought to involve interactions between genetic predisposition, an altered microbiota, and dysregulated immune response, leading to disruption of the intestinal mucosa. A recent study commissioned by Crohn's & Colitis UK have shown one in every 123 people are living with IBD in the UK, increasing to one in every 67 in people aged over 70, with the population living with the condition expected to grow. It is estimated that the total cost of IBD to the NHS is £720 million over a year and lifetime costs to the NHS are comparable to several major diseases, including heart disease or cancer.
CHALLENGE: Oral local delivery of macromolecules offers therapeutic potential for gastrointestinal diseases. However, creating a stable formulation of these target compounds in order to ensure targeted delivery and retention of efficacy is challenging.
PROJECT: In this project we are building on our established research on the use of hydrogels and penetration agents in order to create a stable formulation of protein therapeutics to the GI tract. The work will be broken down into four main work packages; 1) The formulation of the target therapeutics with excipients. In order to protect the proteins from the harsh gastro environment we will utilise hydrogels. The formulation will be characterised and stability testing will be performed. The formulation will then be examined for cytotoxicity in vitro against a range of primary and secondary cells. 2) Penetration studies of the target therapeutic will be performed in cells once the cytotoxicity profile is established. The formulation will be modified to ensure maximum penetration to the target cells. This will allow the technology to be used as a platform technology which can be modified to target different areas of the gastrointestinal tract by modifying its release rate and response to pH stimuli. 3) Once the system is fully characterised in vitro, in vivo delivery studies will be performed using C. elegans nematodes to determine the ability of the formulation to deliver to the gastrointestinal tract. 4) Biological efficacy in the in vivo model will be determined using a combination of transcriptomic and metabolomic analysis. This will utilise sequencing to determine the therapeutic effect of the delivered therapeutic and demonstrate the efficacy of the technology.