Abstract
Contract No.: 305421; EU contribution: € 5,380,169.75; Total costs: € 7,002,945.20; Starting date: 01/01/2013; Duration: 60 months
Background and Objectives
Fanconi anemia (FA) is a rare inherited syndrome characterized by the early development of bone marrow failure and increasing predisposition to cancer with age. Allogeneic hematopoietic cell transplantation is the only curative therapy for hematopoietic manifestations of FA, although associated with complications arising from myeloablation, graft versus host disease, and increased incidence of squamous cell carcinoma. The genetic correction of autologous hematopoietic stem cells (HSCs) with lentiviral vectors (LVs) has been proposed as a safe alternative for the treatment of different genetic diseases affecting mature cells from different tissues and/or committed progenitors of the hematopoietic system. One of the key features of FA that make it a unique disease for gene therapy approaches relies on the characteristic proliferation defect that is already evident in the very primitive HSCs. Thus, a marked survival advantage would be expected from corrected HSCs, potentially allowing normalization of hematopoiesis in the absence or after mild conditioning. Difficulties in the collection of sufficient numbers of HSCs from FA patients and the use of suboptimal transduction protocols with gammaretroviral vectors limited the success of FA gene therapy trials conducted 10 years ago. The main goal of this project is to develop an efficient and safe gene therapy of FA based on two recent innovations: (1) discovery of potent HSC mobilizers, such as plerixafor, and (2) development of a new LV by members of this consortium, designated as “orphan drug” by the European Commission in December 2010.
The principal objective of this project is the development of a phase I/II gene therapy trial for FA-A patients, based on the genetic correction of plerixafor plus G-CSF–mobilized HSCs with a novel FA LV, accompanied by comprehensive and groundbreaking safety and efficacy patient-monitoring studies.
Approach and Methodology
The project is structured in six different Work Packages (WP).
WP1 aims to characterize the genetic and hematopoietic defects of FA patients to facilitate the recruitment for the clinical trials that aim (1) to collect an improved number of HSCs (WP2) and (2) to infuse gene-corrected HSCs in FA patients (WP4).
WP2 aims to implement an optimized procedure for the collection of HSCs from FA patients using an efficient HSC mobilization regimen with plerixafor combined with G-CSF.
WP3 aims to validate the efficacy and safety of clinical GMP batches of the therapeutic LV that will be used in the clinical trial.
WP4 aims to investigate the safety and the efficacy of the infusion of autologous CD34+ cells transduced with the therapeutic LV carrying the FANCA gene (the orphan drug) in FA-A patients.
WP5 carries out the actions for achieving the maximum exploitation and diffusion of EUROFANCOLEN project results.
WP6 aims the appropriate management of the project, together with an adequate dissemination and exploitation of the project results, the convenient management of intellectual property, the assurance of all ethics issues, and finally the development of a convenient gender action plan.
Main Findings
Identification of mutations in FA genes: Pathogenic mutations in 20 out of 22 FA patients have been identified.
Assessment of the safety and efficacy of plerixafor plus G-SCF–mediated mobilization of CD34+ cells: A clinical trial aiming the safety and the efficacy of this mobilization regimen is open, and four patients have been already recruited.
Validation of preclinical gene therapy studies with the therapeutic clinical-grade LV: A clinical lot of the FANCA-LV has been already produced. The batch is used for the validation of the transduction protocol under GMP conditions, as well as for the validation of all the quality controls required by the regulatory agency. To investigate the biosafety of insertion sites of the therapeutic LV, bone marrow cells from Fanca−/− mice were transduced with the therapeutic LV and then transplanted into primary and secondary Fanca−/− mice recipients. The analysis of the dynamics of LV-transduced Fanca−/− repopulating clones showed a highly polyclonal repertoire and a healthy genetic pattern of clonal turnover in transplanted FA mice.
Expected Outcome
The expected final result of EUROFANCOLEN is the development of a new therapy for the bone marrow failure of FA patients. The proposed gene therapy approach would constitute a new therapeutic opportunity for patients lacking a suitable donor, which may additionally circumvent some of the undesired effects of allogeneic bone marrow transplantation.
