2013 - CTS 2013 Congress
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Oral Communications 4
9.5 - Pancreatic islet engraftment is improved by Spiegelmer-based blockade of CXCL12/SDF-1
Presenter: Simona, Marzorati, Milan, Italy
Authors: Simona Marzorati1,2, Antonio Citro1,2, Sven Klussmann1,2, Lorenzo Piemonti1,2
Pancreatic islet engraftment is improved by Spiegelmer-based blockade of CXCL12/SDF-1
Simona Marzorati1,2, Antonio Citro1,2, Sven Klussmann1,2, Lorenzo Piemonti1,2
1Diabetes Research Institute, San Raffaele Hospital, Milan, Italy; 2NOXXON Pharma AG, Berlin, Germany
Background. Blocking proinflammatory mediators is a successful approach to improve the engraftment after islet transplantation. Spiegelmers are biostable mirror-image aptamers that can bind and inhibit target molecules; they represent a non-immunogenic alternative to antibodies. We evaluated whether Spiegelmer-based blockade of CXCL12/SDF-1 is able to favour islet engraftment in murine models.
Methods/Materials.CXCL12/SDF-1 blockade by Spiegelmer NOX-A12 was tested in a syngeneic marginal mass mouse islet transplantation model in which 200 C57BL/6 pancreatic islets are transplanted into liver of diabetic C57BL/6 mice. We also tested all the compounds in diabetes induced by the treatment of multiple low doses of streptozotocin (MLD-STZ), a mouse model in which a beta-cell damage is induced by inflammation.
Results.CXCL12/SDF-1 blockage by NOX-A12 treatment for 15 days was able to significantly improve islet engraftment. The median time to gain normoglycaemia was 4±3 days and 26±34 days for NOX-A12 (n=10) and vehicle (n=10) treated mice, respectively (p=0.004). Multivariate Cox Regression analysis confirmed NOX-A12 treatment as a significant favourable factor for the engraftment after the correction for pre-transplant glycaemia (HR: 6.4; 95% CI: 1.5-25.4; p=0.009). Concordantly, NOX-A12 treatment was able to protect islets by the inflammation-mediated damage in the MLD-STZ model: the median diabetes-free time was 20±2 days and 33±6.9 days for vehicle (n=12) and NOX-A12 (n=12) treated mice, respectively (HR: 0.296; 95% CI: 0.092-0.945; p=0.04).
Conclusion.CXCL12/SDF-1 blockage by the Spiegelmer NOX-A12 resulted in an efficient strategy to improve islet engraftment
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