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GENETIC TREATMENT OF THE HAEMOGLOINOPATHIES: RECOMBINATIONS AND NEW COMBINATIONS

The genetic treatment of severe b-globin disorders is an objective that goes back to the origins of gene therapy. Thalassaemias and sickle cell disease were among the earliest diseases characterized at the molecular level; the globins were among the first human proteins for which the structures were solved; the globin genes and their proximal transcriptional control elements were among those first cloned and characterized in mammalian cells. It is therefore not surprising that the haematologists and geneticists who began to conceive of how to treat diseases by genetic means thought of the globin disorders as model diseases. As severe congenital monogenic disorders, the thalassaemias and sickle cell disease appeared indeed as ‘simple disease[s] with no cure’ (Luzzatto & Goodfellow, 1989) and ideal candidates for gene therapy. This vision was supported by a series of studies in the late 1980s that demonstrated tissuespecific expression of a retrovirally encoded human b-globin gene in murine bone marrow chimaeras (Karlsson et al, 1988; Dzierzak et al, 1988; Miller et al, 1988; Bender et al, 1989). However, low levels of gene transfer and gene expression turned out to be intractable obstacles to any clinical application. Other diseases with less stringent requirements for gene expression soon became the focus of greater attention and greater hopes for curing a severe disorder using a genetic approach. Recent progress in our understanding of the transcriptional control and the chromatin organization of the aand b-globin gene clusters (Grosveld et al, 1993; Orkin, 1995; Stamatoyannopoulos, 1995), together with advances in gene transfer biology and the utilization of recombination of nucleic acids, are renewing the excitement in the genetic treatment of the haemoglobinopathies. The latter remains the paradigm for genetic approaches that aim to durably correct the expression of a tissue-specific gene at the level of haemopoietic stem cells. This review summarizes recent findings and highlights the remaining obstacles that determine the current prospects of this therapeutic approach.