Project: Adipose tissue-derived mesenchymal stem cells for clinical application

Adipose tissue-derived mesenchymal stem cells for clinical application

This is a summary of the request.

Bone marrow mesenchymal stem cell therapy is a promising new modality of cell therapy, which is currently explored in several clinical conditions. While bone marrow-derived MSCs are the main source for MSC treatment, adipose tissue-derived MSCs represent a novel and more practical source, since the higher number of MSC in this tissue and the higher proliferative potential allow more rapid expansion to therapeutic quantities. It is still largely unknown however to what extend the functional properties of these cells are different from bone-marrow derived MSCs (BM-MSCs). Here we propose to perform a detailed characterization and comparison of adipose tissue-derived MSCs (AT-MSCs) with BM-MSCs. Primary (Stromal Vascular Fraction) and culture-expanded (subsets of) AT-MSCs will be expanded under different culture conditions and will be functionally characterized in vitro with respect to their proliferative, anti-inflammatory, immunomodulatory and proangiogenic properties and compared with primary adipose tissue derived cells and BM-MSCs Extensive safety studies will be performed in-vitro and in-vivo, including in-vivo survival and homing, ectopic tissue formation and tumour formation. Based on these data a preferential subset or unselected culture-expanded AT MSCs will be selected for upscaling and robust GMP production (pharmaceutic phase). Following validation and safety testing of the product, CCMO approval will be requested. GMP expanded AT-MSCs will be released for clinical application in a phase I/II study in patients with chronic refractory angina pectoris due to myocardial ischemia ( the clinical phase B). We have recently completed a double blind randomized, placebo-controlled trial in these patients. Bone marrow-derived mononuclear cells were found to reduce myocardial ischemia and symptoms, while improving exercise tolerance and cardiac function. Our project will thus introduce a novel MSC source for a novel clinical application of MSCs. At the same time, the clinical comparison with historical but similar patients treated with BM mononuclear cells will become possible. Giving the robust proangiogenic potential of MSCs in experimental ischemia models, we will use small amounts of the clinical AT-MSCs product to study their angiogenic potential in an animal model. A possible correlation between clinical outcome and in-vivo proangiogenic potential will serve as a retrospective validation of the mouse model to predict outcome in patients.