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Cure of experimental Laron syndrome (LS) by microencapsulated Sertoli cell (SC) xenograft

Giovanni Luca¹, Mario Calvitti¹, Giulia Falabella¹, Catia Bellucci¹, Francesca Mancuso¹, Darlene Berryman², Iva Arato¹, Edward List², Ennio Becchetti¹, John Kopchick², Tiziano Baroni¹, Riccardo Calafiore³

¹Experimental Medicine and Biochemical Sciences; ³Internal Medicine, University of Perugia, Perugia, Italy; ²School of Human and Consumer Sciences, Ohio University, Athens, OH, United States

LS is a rare human inherited disorder caused by defects in the gene encoding the growth hormone (GH) receptor, with consequential suppression of IGF-1 production, leading to clinical dwarfism. The only actual available therapy consists of recombinant human IGF−1, injected daily, which unfortunately is burdened with side effects, other than being an “orphan drug”, hence poorly available for treating LS patients. Since IGF-1 is one of the most important SC secretory products, we aimed to determine if alginate-encapsulated SC transplant (TX) would reverse GH deficiency in “Laron mice” (LM), a unique animal model of genetic GH deficiency, identical to human LS. 60 LM were grafted with encapsulated SC, while 20 untreated LM served as controls. SC, upon retrieval from pre-pubertal pigs, were enveloped in Barium-AG microcapsules (BaMCs), according to our methods. BaMCs were examined as far as: (a) SC morphology by light microscopy; (b) SC viability, by fluorescence microscopy after staining with ethidium bromide and fluorescein diacetate (EB+FDA); (c) pre-TX SC in vitro function (alpha-aromatase activity and IGF-I secretion); (d) post-TX inducedgrowth parameters in LM, were concerned. BaMCs exhibited excellent physical-chemical features, while the enveloped SC showed excellent viability (over 90%) and function in terms of a-aromatase activity and IGF-I secretion, prior to TX. Intraperitoneal TX of BaMCs into LM induced significant increase in growth parameters, in terms of body weight and nose -to-anus length, exceeding by 20% those of untreated controls. All retrieved organs showed significant growth as compared to those of untreated LM, indicating full correction of the GH deficiency. In conclusion, xenograft of morphologically intact and functionally competent SC with Ba-AG microcapsules into homozygous LM with overt dwarfism, induced an unprecedented and significant increase in all growth parameters in comparison with untreated controls.This result might definitely open new perspectives for the cure of human LS.