Introduction

Fanconi's anemia (FA) is a genetic syndrome that leads to bone marrow failure, congenital anomalies, and a predisposition to cancer in affected individuals (Fanconi, 1927, 1967). FA's clinical features and genetic basis, as well as the conventional approaches to treating FA patients, are detailed in Chapters 17–19. The purpose of this review is to summarize both the rationale and the progress of gene therapy strategies aimed at correcting the hemopoietic defect of FA, usually manifesting as aplastic bone marrow failure.

FA is thought to affect the hemopoietic stem cell (HSC), as evidenced by profoundly diminished numbers of platelets, erythrocytes, and granulocytes in patients. As a stem-cell disorder, the hemopoietic consequences of FA can be effectively treated by complete replacement of the patient's stem cells with those from a histocompatible donor (Gluckman et al., 1989, 1995; Kohli–Kumar et al., 1993). Pretreatment with chemotherapy and irradiation is required to destroy the diseased marrow as well as to suppress the patient's immune system so that it cannot reject the transplanted stem cells. Historically, this has been difficult to accomplish in FA patients since they are particularly sensitive to these toxic agents. Doses of therapy typically required to eliminate a patient's immune system cannot routinely be given, and, at this time, an individual patient's sensitivity to the chemotherapy and irradiation cannot be predicted. Even with the lower doses of therapy given today, some patients are inordinately sensitive and will die as a result of organ failure.