1. ¹Fanconi Anemia Comprehensive Care Center, Divisions of Experimental Hematology and Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
2. ²National Center for Tumor Diseases, German Cancer Center, Heidelberg, Germany
3. ³Department of Pediatrics, University of Cincinnati College of Medicine and Academic Health Center, Hoxworth Blood Center, Cincinnati, Ohio, USA
4. ⁴Laboratory of Human Genetics and Hematology, The Rockefeller University, New York, New York, USA

Correspondence: David A Williams, Fanconi Anemia Comprehensive Care Center, Divisions of Experimental Hematology and Hematology/Oncology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, ML 7013, Cincinnati, Ohio 45215, USA. E-mail: David.Williams@cchmc.org

Received 17 July 2006; Accepted 14 August 2006.

Abstract

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34⁺ stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34⁺ cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34⁺ cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials.