Preclinical study for treatment of hypospadias by advanced therapy medicinal products.

V Sceberras,C Trombetta,M Rizzo,L Losi,M Lazzeri,G Galaverni,S Balò,F Corradini,A Ribbene,M Fantacci,R Manfredini,G Barbagli,M Melonari,G Pellegrini,E Attico,E Bianchi

doi:10.1007/s00345-019-02864-x

Abstract

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. 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. 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. Against this backdrop, in this paper, we are proposing a new reproducible and reliable ATMP for the treatment of hypospadias.

Highlights

Hypospadias, one of the most common congenital malformations of male genitals with an incidence of 1 out of 1000 male births (Orphanet 440), is defined by an abortive development of the urethral corpus spongiosum, ventral prepuce, and arrest in the normal embryological development of the urethra [1]
The final tissue constructs consisted of modified fibrin glue scaffolds (EP Patent 1451302) covered by adhering ex vivo expanded autologous human epithelia
The clinical trial (EudraCT number 2017-000361-78) will involve male pediatric and adult patients suffering from reduced urethral functionality and/or distal and recurrent lesions in a very large part of urethra due to failure of primary hypospadias repair

Summary

Introduction

Hypospadias, one of the most common congenital malformations of male genitals with an incidence of 1 out of 1000 male births (Orphanet 440), is defined by an abortive development of the urethral corpus spongiosum, ventral prepuce, and arrest in the normal embryological development of the urethra [1] Problems related to this disease include altered urination and ejaculation and psychological problems causing depression and disability. Mechanical irritation from dental rubbing and parafunctional biting of the oral mucosa increases the chances of oral cancer development [8] This practice only allows two big tissue removals from the oral mucosa, but the aforementioned procedures require repeated surgery in approximately half of the patients [9]. When supplied with stem cells, the resulting cultured tissue can engraft and persist at the desired location, self-renewing over the lifetime and restoring missing functionality [10]

Methods

Results

Conclusion