Phase I/II Gene Therapy Trial of Fanconi Anemia Patients with a New Orphan Drug Consisting of a Lentiviral Vector Carrying the FANCA Gene: A Coordinated International Action (EuroFancolen)

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.