BOne marrOw transfer to enhance ST-elevation infarct regeneration-2
Final Report Abstract
Patients with severely reduced heart function after ST-elevation myocardial infarction (STEMI) continue to be at risk of heart failure and premature death. In 2004, the open-label BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial was the first of a series of randomised-controlled clinical trials demonstrating that an intracoronary infusion of autologous bone marrow cells (BMCs) enhances the recovery of heart function after STEMI. Lately, several studies did not confirm such therapeutic effects. Some of this heterogeneity has been attributed to differences in cell isolation protocols across trials. Moreover, recent improvements in patient management and long-term medical treatment may have made it more difficult for BMC therapies to provide incremental benefit. Using the cell isolation protocol from the BOOST trail, we have now reevaluated this strategy in the randomised placebo-controlled, double-blind BOOST-2 trial which was conducted in 10 centres in Germany and Norway. Using a multiple arm design, we investigated the doseresponse relationship and explored, for the first time, whether γ-irradiation, which eliminates the clonogenic potential of stem and progenitor cells while preserving cell viability, has an impact on BMC efficacy. Treatment with clonogenic or non-clonogenic BMCs did not improve heart function in BOOST-2. Accordingly, BOOST-2 does not support the use of BMCs in patients with STEMI treated according to current standards of immediate revascularisation and drug therapy. The BOOST-2 trial provides an important reassessment of BMC therapy in a contemporary clinical setting. The BOOST-2 trial provided us with the unique opportunity to explore the secretory activity of BMCs in patients with acute myocardial infarction. We observed that BMCs secrete a large number of angiogenic and cytoprotective factors. We have tested the hypothesis that some of these proteins can be developed as therapeutic agents. Indeed, we identified a previously uncharacterized secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promoted cardiac myocyte survival and angiogenesis. We named this protein myeloid-derived growth factor (HUGO Gene Nomenclature Committee-approved symbol: MYDGF). We found that subcutaneous treatment with recombinant MYDGF reduces scar size and protects from heart failure after myocardial infarction in mice. We have applied for a patent describing the therapeutic use of MYDGF, and another angiogenic protein that we also identified in human BMCs. We have started a collaboration with a big pharma company to develop MYDGF towards clinical application.
Publications
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Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction. Eur Heart J 2008;29:2851-8
Korf-Klingebiel M, Kempf T, Sauer T, Brinkmann E, Fischer P, Meyer GP, Ganser A, Drexler H, Wollert KC
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Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. Circulation 2011;123:504-14
Korf-Klingebiel M, Kempf T, Schlüter KD, Willenbockel C, Brod T, Heineke J, Schmidt VJ, Jantzen F, Brandes RP, Sugden PH, Drexler H, Molkentin JD, Wollert KC
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Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nature Med 2015;21:140-9
Korf-Klingebiel M, Reboll MR, Klede S, Brod T, Pich A, Polten F, Napp LC, Bauersachs J, Ganser A, Brinkmann E, Reimann I, Kempf T, Niessen HW, Mizrahi J, Schönfeld HJ, Iglesias A, Bobadilla M, Wang Y, Wollert KC
