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EUSTACHIO ATTICO

Ricercatore t.d. art. 24 c. 3 lett. A
Dipartimento di Scienze della Vita sede Centro di Medicina Rigenerativa
COLLABORATORE COORDINATO CONTINUATIVO
Centro Interdipartimentale Cellule Staminali e Medicina Rigenerativa (CIDSTEM)

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Pubblicazioni

2023 - Comparison between Cultivated Oral Mucosa and Ocular Surface Epithelia for COMET Patients Follow-Up [Articolo su rivista]
Attico, Eustachio; Galaverni, Giulia; Torello, Andrea; Bianchi, Elisa; Bonacorsi, Susanna; Losi, Lorena; Manfredini, Rossella; Lambiase, Alessandro; Rama, Paolo; Pellegrini, Graziella
abstract

Total bilateral Limbal Stem Cell Deficiency is a pathologic condition of the ocular surface due to the loss of corneal stem cells. Cultivated oral mucosa epithelial transplantation (COMET) is the only autologous successful treatment for this pathology in clinical application, although abnormal peripheric corneal vascularization often occurs. Properly characterizing the regenerated ocular surface is needed for a reliable follow-up. So far, the univocal identification of transplanted oral mucosa has been challenging. Previously proposed markers were shown to be co-expressed by different ocular surface epithelia in a homeostatic or perturbated environment. In this study, we compared the transcriptome profile of human oral mucosa, limbal and conjunctival cultured holoclones, identifying Paired Like Homeodomain 2 (PITX2) as a new marker that univocally distinguishes the transplanted oral tissue from the other epithelia. We validated PITX2 at RNA and protein levels to investigate 10-year follow-up corneal samples derived from a COMET-treated aniridic patient. Moreover, we found novel angiogenesis-related factors that were differentially expressed in the three epithelia and instrumental in explaining the neovascularization in COMET-treated patients. These results will support the follow-up analysis of patients transplanted with oral mucosa and provide new tools to understand the regeneration mechanism of transplanted corneas.

2023 - Education for the translation of Advanced Therapy Medicinal Products [Articolo su rivista]
Adamo, Davide; Attico, Eustachio; Pellegrini, Graziella
abstract

2022 - SOX2 Is a Univocal Marker for Human Oral Mucosa Epithelium Useful in Post-COMET Patient Characterization [Articolo su rivista]
Attico, Eustachio; Galaverni, Giulia; Bianchi, Elisa; Losi, Lorena; Manfredini, Rossella; Lambiase, Alessandro; Rama, Paolo; Pellegrini, Graziella
abstract

Total bilateral Limbal Stem Cells Deficiency is a pathologic condition of the ocular surface due to loss or impairment of corneal stem cell function, altering homeostasis of the corneal epithelium. Cultivated Oral Mucosa Epithelial Transplantation (COMET) is the only autologous treatment for this pathology. During the follow-up, a proper characterization of the transplanted oral mucosa on the ocular surface supports understanding the regenerative process. The previously proposed markers for oral mucosa identification (e.g., keratins 3 and 13) are co-expressed by corneal and conjunctival epithelia. Here, we propose a new specific marker to distinguish human oral mucosa from the epithelia of the ocular surface. We compared the transcriptome of holoclones (stem cells) from the human oral mucosa, limbal and conjunctival cultures by microarray assay. High expression of SOX2 identified the oral mucosa vs. cornea and conjunctiva, while PAX6 was highly expressed in corneal and conjunctival epithelia. The transcripts were validated by qPCR, and immunological methods identified the related proteins. Finally, the proposed markers were used to analyze a 10-year follow-up aniridic patient treated by COMET. These findings will support the follow-up analysis of COMET treated patients and help to shed light on the mechanism of corneal repair and regeneration.

2022 - The cell as a tool to understand and repair urethra [Capitolo/Saggio]
Sceberras, Virginia; Maria Magrelli, Federica; Adamo, Davide; Maurizi, Eleonora; Attico, Eustachio; Giuseppe Genna, Vincenzo; Lazzeri, Massimo; Barbagli, Guido; Pellegrini, Graziella
abstract

2021 - Clinical Studies of COMET for Total LSCD: a Review of the Methods and Molecular Markers for Follow-Up Characterizations [Articolo su rivista]
Attico, Eustachio; Galaverni, Giulia; Pellegrini, Graziella
abstract

Purpose of Review This review outlines the main features of the clinical trials where cultivated oral mucosa epithelial cell transplantation (COMET) was performed, aiming to underscore a link between the clinical outcome and the expression of specific markers during the follow-up of patients, characteristic for a defined epithelium (cornea, oral mucosa, or conjunctiva) or related to vascularization. Recent Findings Currently, little is known about the reasons underlying the success or failure of COMET. To address this issue, we focused on tissue characterization at the molecular level, highlighting the findings concerning angiogenesis. Summary There are several discrepancies in the outcomes of COMET clinical trials. While some corneal/conjunctival markers can be considered reliable for understanding the biological mechanisms that drive corneal repair after transplants, a unique marker specifically expressed in the oral mucosa and an accurate study of the vascularization processes are currently missing. Together, these insights will help forecast successes and failures of these technologies.

2021 - Regenerative Medicine of Epithelia: Lessons From the Past and Future Goals [Articolo su rivista]
Maurizi, Eleonora; Adamo, Davide; Magrelli, FEDERICA MARIA; Galaverni, Giulia; Attico, Eustachio; Merra, Alessia; Maffezzoni, MARIA BENEDETTA RIZZARDA; Losi, Lorena; Genna, VINCENZO GIUSEPPE; Sceberras, Virginia; Pellegrini, Graziella
abstract

This article explores examples of successful and unsuccessful regenerative medicine on human epithelia. To evaluate the applications of the first regenerated tissues, the analysis of the past successes and failures addresses some pending issues and lay the groundwork for developing new therapies. Research should still be encouraged to fill the gap between pathologies, clinical applications and what regenerative medicine can attain with current knowledge.

2020 - Preclinical study for treatment of hypospadias by advanced therapy medicinal products [Articolo su rivista]
Sceberras, V.; Attico, E.; Bianchi, E.; Galaverni, G.; Melonari, M.; Corradini, F.; Fantacci, M.; Ribbene, A.; Losi, L.; Balò, S.; Lazzeri, M.; Trombetta, C.; Rizzo, M.; Manfredini, R.; Barbagli, G.; Pellegrini, G.
abstract

Purpose This paper explores the feasibility of a new therapy for the treatment of hypospadias patients. Hypospadias is a very common congenital malformation of male genitals, with very high rate of recurrences after surgery. The field of regenerative medicine, which offers innovative solutions for many pathologies, still does not offer reliable solution for this pathology. Here, we propose quality, safety, and clinical feasibility assessment for an oral mucosa advanced therapy medicinal product (ATMP) grown on a biocompatible scaffold for a clinical study on urethral reconstruction of hypospadias patients. Methods Urethral and oral mucosal epithelia from donor biopsies were cultivated between two fibrin layers, under clinical-grade conditions for cell and tissue characterization and comparison, aimed at tissue engineering. In addition, single-clone analyses were performed to analyze gene expression profiles of the two epithelia by microarray technology. Results Oral mucosa appeared suitable for urethral reconstruction. The resulting ATMP was proven to maintain stem cells and regenerative potency. The preclinical safety studies were performed on human tissues to assess abnormalities and tumorigenicity, and confirmed the safety of the ATMP. Finally, the patient selection and the clinical protocol for the upcoming clinical trial were defined. Conclusions Against this backdrop, in this paper, we are proposing a new reproducible and reliable ATMP for the treatment of hypospadias.

2019 - Stem Cells and Ocular Regeneration. [Capitolo/Saggio]
Attico, E.; Chiavelli, Chiara; Sceberras, V.; Fantacci, M.; Melonari, M.; Pellegrini, Graziella
abstract

The surface of the eye is a peculiar and extraordinary area, since the functions of all regions of the ocular surface system (OSS) are closely integrated forming a unique functional unit composed of different tissues and organs. Anatomically the ocular surface is composed principally by cornea and conjunctiva, but it also includes the lacrimal gland and the lacrimal drainage system for the tear film homeostasis, and the eyelids. Additional components as Meibomian glands, eyelashes and eyebrows complete the picture, contributing to the outermost lipid layer and to particle clearance (Fig. 1). Cornea and conjunc- tiva are generally covered by a complex liquid known as the tear film, providing a continuous moist environment connecting all areas at the front of the eye ball and protecting them from pathogens and small solid particles. This interconnected system provides the necessary conditions for the maintenance of functions needed for the vision process, as the final goal of eye function. The dysfunction of this apparatus could lead to several pathologies, such as corneal opacity or dry eye diseases (DED). Each component plays an important role for ocular surface maintenance, therefore some recent findings in stem cell biology aimed at the regeneration of different components of the ocular surface by tissue engineering, are examined in the following paragraphs.

2018 - Approaches for Effective Clinical Application of Stem Cell Transplantation [Articolo su rivista]
Attico, Eustachio; Sceberras, VIRGINIA SIDONIA; Pellegrini, G.
abstract

Purpose of Review: This review highlights problems related to translation of advanced therapy medicinal products (ATMPs) from bench to bedsite. Regenerative medicine within the current regulatory frame reveals common hitches in the course of development, translation, and clinical application. This paper suggests outlining a path from the few examples of successfully approved vs unsuccessful advanced therapies. Recent Findings: In the multitude of ongoing studies, few of them achieved positive results with a final treatment available to patients; this result was possible due to multidisciplinary teams working together from the beginning of the development and during the hard route to standardization and clinical application. Summary: The root of success of an advanced therapy requires not only the inescapable scientific and biological knowledge but also requires several contributions as regulatory, ethical, medical, and bio-engineering expertise, from the real beginning. A strong scientific rationale and an integrated network of expertises would contribute to a successful investment of available resources in advanced therapy medicinal products and to a greater confidence in future medicine.