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Translational research for the clinical use of insulin secreting cells generated by epigenetic conversion

We recently developed a method for the epigenetic conversion of human dermal fibroblasts into insulin secreting cells (epiCC). The method is based on a brief exposure (18 h) to the demethylating drug 5-aza-cytidine (5-aza-CR) followed by a 3-step differentiation protocol (PNAS, 2013, 110: 8948¿8953). This methods has notable advantages compared to the alternative available procedures: it is highly efficient (>35% conversion rate), it does not require any transgenic modification, it does not induce a stable pluripotent stage, preliminary data show no evidence of tumorigenic transformation, it is patient-specific and therefore it avoids allogeneic rejection. For all these reason epiCC are promising candidates for clinical translation as a therapy for type I diabetes mellitus (T1DM). The objective of this project is to determine if epiCC are safe and effective for clinical use through experiment in relevant animal models. To determine the safety we will test the risk of malignant transformation injecting human epiCC in SCID mice and injecting luciferase labelled mouse epiCC in syngeneic mice. We will verify the possible requirement for a device to contain epiCC at the injection site by performing accurate autopsy of all organs and lymph nodes 50 weeks upon transplantation. The ability of epiCC to self-regulate and do not cause hypoglycaemia will be determined injecting human and mouse epiCC in healthy mice. To determine the efficacy of epiCC we will test their ability to maintain glycaemic levels within the physiological range in NOD mice and in spontaneously diabetic dogs. We will test the possibility to revert a gradual destruction of insulin secreting epiCC by autoimmune mechanisms, performing repeated injection in the same patient. We will determine the minimal effective dose by testing decreasing doses of mice epiCC in F1 outbred mice as a relevant model for the human population.

Principal Investigators:
  • tiziana BREVINI
Financing institution:
EUROPEAN FOUNDATION FOR THE STUDY OF DIABETES - EFSD
Type:
INTLI - Finanziamenti internazionali
Project leader:
UNIVERSITA' DEGLI STUDI DI MILANO
Year:
2014
Duration:
33
Status:
CHIUSO
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