PI David Hackam, MD, PhD and John March, PhD
Title Generation of an Artificial Intestine for the Treatment of Short Bowel Syndrome in Children
Description The clinical condition in which the body is unable to absorb food after significant loss of the intestine is called short bowel syndrome (SBS). While its true incidence is unknown, in the United States the condition affects over 5000 children, with an estimated 15,000 older patients requiring long-term home parenteral nutrition. SBS can be caused by loss of large portions of functioning intestine – such as occurs typically as a consequence of necrotizing enterocolitis (NEC), Crohn’s disease, or as a result of a birth defect in which the intestines do not develop normally. Because food cannot be adequately absorbed by the shortened intestine, nutrients must be administered directly into the circulation through a vein. Although this approach can supply adequate calories, children who receive nutrition directly into the circulation commonly suffer from intravenous catheter infections and severe liver toxicity, with mortality around 30%. Only about one third of patients with SBS can expect to be weaned from parenteral nutrition. The majority of children with short bowel syndrome require intestinal transplantation and if toxicity from the administered nutrition is severe enough, liver transplantation, as well. While the outcome after intestinal transplantation is improving, this procedure is limited by a lack of suitable donors and complications from immunosuppressive therapy. To address the difficulty of managing short bowel syndrome in children, Hackam and March propose constructing an artificial intestine using cultured intestinal stem cells from the recipient’s intestine that can grow on a synthetic 3-dimensional bioscaffold.
Based upon his discovery that expression and signaling activity of a molecular “switch” called toll-like receptor 4 (TLR4) was elevated in the intestine of human infants with NEC and that mice lacking TLR4 were protected from the development of NEC, Hackam proposed as a 2008 Hartwell Investigator to identify novel chemical compounds for the treatment of the disorder. He deployed a strategy to identify specific inhibitors of TLR4 signaling in the intestine utilizing high throughput computer-aided screening of chemical libraries, combined with whole animal screening. He successfully identified 67 novel TLR4 inhibitors, with one compound particularly effective in reducing the severity of experimentally induced NEC in mice. He is now focused on confirming the mechanism of action of the compound, while performing chemical modification to improve it as a powerful new treatment for the management of NEC in neonates.
Source The Hartwell Foundation
Amount $543,571 in direct costs over three years