EuroFancolen Project Description

cellThe genetic correction of autologous hematopoietic stem cells (HSC) with lentiviral vectors constitutes a recent and 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 rely 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 HSC from FA patients and the use of sub-optimal transduction protocols with gammaretroviral vectors limited the success of FA gene therapy trials conducted 10 years ago in the USA.

Our innovative approach to develop for the first time an efficient and safe gene therapy of FA is based on two recent innovations:
   1) Discovery of potent HSC mobilizers, such as plerixafor, and
   2) Development of a new lentiviral vector by members of this Consortium, designed as Orphan Drug by the EC in December 2010.

Look at the illustration below to know work packages (WP) interdependiences of EuroFancolen. WP details are given after the picture:

work packages interdependence

work package 1

Genetic and hematopoietic studies for the recruitment of FA patients in the stem cell collection (WP2) and gene therapy (WP4) trials.

In WP 1, a comprehensive genetic and hematopoietic screening will be conducted in FA patients, prior to their recruitment in the planned clinical trials. In these patients, cytogenetic, genetic and hematopoietic studies will be conducted aiming to verify which of these patients fit the inclusion criteria required for the collection (and in many cases cryopreservation) their HSCs (clinical trial #1; WP2) and thereafter for the re-infusion of autologous gene corrected HSCs (CD34+ cells; clinical trial #2; WP4). All these diagnostic activities (cytogenetic; subtyping; mutation screening; somatic mosaicism and hematopoietic) will be conducted in a centralized manner by Partners P8 (WP coordinator; UAB), P1 (CIEMAT) and P7 (UPD). All analyzed parameters will be included in the EUROFANCOLEN Registry.

work package 2

Assessment of the safety and efficacy of plerixafor plus G-SCF–mediated mobilization of CD34+ cells

As the diagnostic studies progress, WP2 will be initiated. In this WP, different inter-related tasks will be developed sequentially. Because of the very limited experience of mobilizing CD34+ cells in FA patients with plerixafor and G-CSF, a multicentric clinical trial will be developed to assess the safety and efficacy of this mobilization regimen in FA patients. After approval by the Regulatory Agencies, the multicentric clinical trial will be conducted by P3 (WP coordinator, UCL), P2 (AP-HP), P4 (SERMAS) and P5 (ICS-HUVH). Patients will be treated with plerixafor/G-SCF to facilitate the mobilization, collection, purification, and in most cases the cryopreservation of CD34+ cells. Twenty FA patients are planned to be recruited in this first clinical trial. The reason for conducting a separated clinical trial for the collection and another one for the re-infusion of the corrected stem cells in the patient derives from the fact that different inclusion/exclusion criteria will define the patients that are recruited for each clinical trial. While the efficient collection of HSCs will essentially be feasible in non aplastic patients, the infusion of gene corrected stem cells would preferentially be conducted in patients with evidences of BMF.

work package 3

Validation of preclinical gene therapy studies with the therapeutic clinical-grade lentiviral vector (Orphan drug for FA-A patients)

In parallel with the collection of the CD34+ cells, WP3 aiming to validate the transduction conditions already achieved with a pre-GMP batch of the therapeutic vector will be conducted using the clinical vector batch. These studies will be included in the dossier required for the approval of the gene therapy trial corresponding to WP 4. P4 (GENETHON) will take the responsibility of a critical part of the project consistent on the manufacturing of the clinical batch of the therapeutic lentiviral vector. This Institution has already generated a pre-GMP batch for P1 (CIEMAT) to conduct the prevalidation studies.

work package 4

Assessment of the safety and efficacy of the infusion of gene-corrected  CD34+ cells in FA-A patients

The progress of WP1 and WP3 will allow us to prepare the dossier of the gene therapy clinical trial corresponding to WP4. Once approved the multicentric trial in the different Regulatory Agencies, cryopreserved - or in some instances fresh - CD34+ cells collected in WP2 will be gene corrected and then infused in a total of 10 FA patients showing clinical evidences of BMF by the clinical partners, P2 (WP coordinator; AP-HP), P3 (UCL), P4 (SERMAS) and P5 (ICS-HUVH). After the infusion of the gene corrected cells, safety studies based on the investigation of the insertion sites along the post-transplantation period will be conducted by P9 (GATC) and P10 (DKFZ). Also analyses of the engraftment of genotypic and phenotypic corrected cells will be conducted.

work packages interdependence second part

Complementarities and Interaction of EUROFANCOLEN Partners for the progress of the Project throughout the different WPs.