Inflammatory bowel disease (IBD) which includes Crohn's disease and ulcerative colitis affects about 1.4 million patients in the United States, including many children and young adults. It is characterized by extensive inflammatory changes in the bowel wall with overexpression of molecular inflammation markers such as P- selectin on vascular endothelial cells in the bowel wall. Due to the chronicity of IBD with multipl relapses and long treatment phases including drugs such as immunosuppressants and -modulators that are associated with major side-effects, regular and accurate monitoring of the disease's activity is of paramount importance. Since multiple follow-up exams are needed, often over many years, monitoring should be noninvasive and, above all, patient-friendly. Currently, a simple technique that meets all these requirements is not available. Ultrasound (US) is a non-invasive imaging approach that already meets many of those requirements because 1) it is widely available at relatively low cost, and 2) it does not expose patients to ionizing irradiation (which is very important for repetitive examinations in particular in children and young adults). However, current US technology lacks the sensitivity and specificity to accurately quantify inflammation in the bowel wall. Furthermore, imaging the bowel with US can be technically challenging (e.g., spatial orientation within the large volume of the bowel, possible artifacts fro intraluminal gas, motion, etc). In this grant proposal we combine the advantages of US with those of molecular imaging and develop a molecular US imaging strategy using novel contrast microbubbles that allow inflammation imaging at the molecular level. We have designed a clinical grade microbubble that targets the inflammation marker P-selectin (P-MB) with the goal to transition molecular US for monitoring inflammation into clinical trials.
In specific aim 1, we will test molecular US using novel clinical grade P-MB for imaging and quantification of inflammation at the molecular level in a murine IBD model.
In specific aim 2, we will compare its potential for monitoring inflammation in IBD to 18FDG-PET-CT and DCE-MRI, using ex vivo assays as the gold standard.
In specific aim 3, we will translate our imaging approach from small to large animals in a porcine IBD model as a further step towards clinical translation. Critical data on the feasibility of an optimized molecular US imaging approach in porcine models of IBD (including terminal ileitis and colitis) will be obtained including the opportunity to correate in vivo imaging signals with ex vivo P- selectin expression levels and assessing optimal dosing of novel P-MB in pigs before eventual translation of our novel imaging approach into first-in-human clinical trials. We will also develop and test a novel real-time fused MRI/molecular US imaging approach of the bowel, addressing anticipated challenges when eventually translating molecular US imaging into the clinic, such as the need to image a large volume to obtain representative images of inflamed bowel segments, along with spatial orientation to reliably localize inflamed bowel segments within the large field of view of the bowel, as well as the need to reduce possible artifacts from intraluminal gas and motion. Following successful completion of our research aims, we anticipate rapid translation of this patient-friendly, non-invasive and quantitative imaging technique into the clinic to improve clinical management and outcome of patients with IBD.
Current strategies for monitoring the disease's activity in patients with inflammatory bowel disease (IBD) have major limitations largely hampering personalized clinical management. In this research proposal, we will test the accuracy of a new targeted ultrasound imaging approach that allows non-invasive monitoring of inflammation in IBD at the molecular level without the use of radiation. The successful completion of our aims will lead to the development of a new imaging approach that can be used to more accurately monitor inflammation of the bowel in patients with IBD.
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|Wang, Huaijun; Machtaler, Steven; Bettinger, Thierry et al. (2013) Molecular imaging of inflammation in inflammatory bowel disease with a clinically translatable dual-selectin-targeted US contrast agent: comparison with FDG PET/CT in a mouse model. Radiology 267:818-29|