Abstract
Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene LAMB3 has been the first genetic skin disease successfully tackled by ex vivo gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of LAMB3-related JEB. Autologous clonogenic keratinocytes will be isolated from patients’ skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human LAMB3 cDNA and plated onto a fibrin support (144cm2). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with LAMB3 mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses.Clinical Trial Registration: EudraCT Number: 2018-000261-36.
Highlights
Epidermolysis bullosa (EB) is a heterogeneous group of rare, genetic disorders caused by molecular defects in genes encoding several structural proteins that form the epidermal-dermal junction
We present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of LAMB3-related junctional EB (JEB)
Based on the level of skin cleavage, EB can be classified into four major types – EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome – that differ in severity and prevalence
Summary
Epidermolysis bullosa (EB) is a heterogeneous group of rare, genetic disorders caused by molecular defects in genes encoding several structural proteins that form the epidermal-dermal junction. Given the high likelihood of JEB and RDEB patients to develop aggressive SCC, often leading to their premature death, the rationale for performing this trial in children – besides the obvious advantage of promptly restoring a functional epidermis, preventing recurrent blisters, erosion, and chronic inflammation – arises from the likely assumption that gene therapy could decrease the risk of skin cancer development in the transplanted areas. Despite these encouraging preliminary results, such experimental approaches are still far from a routine therapy. This clinical trial would pave the way for the approval of Hologene 5 as a therapeutic option for at least one subgroup of patients with intermediate JEB
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
