Clinical application of intrauterine bone marrow transplantation for treatment of genetic diseases - Feasibility studies

Intrauterine bone marrow transplantation (BMT) may represent a new approach for correction of a large variety of genetic disorders in utero. The procedure may become feasible for more genetic disorders in the future, since a large majority of potentially correctible diseases can be diagnosed at an early stage of gestation in utero using molecular probes that permit analysis of small biologic samples and even few cells that may be obtained by chorionic villi biopsy and/or amniocentesis. Haploiderltical paternal marrow (2 cases) and sibling bone marrow cells from a disease-free family members, were infused into the fetus. GVHD was avoided following in vitro T-lymphocyte depletion using monoclonal antilymphocyte (CDW52) antibodies (Campath-1) affecting stem cell viability, similarly to the procedures in routine use in clinical BMT programs in man. Three women underwent iutrauterine BMT at 34, 23 and 25 weeks of gestation for metachromatic leucodystrophy (Arylsulfatase A deficiency, 2 cases) and beta thalassemia major (1 case), respectively. A total of 33 x 10⁸, 30 x 10⁸ and 30 x 10⁸ bone marrow cells were infused intraperitoneally (1 case), intraportally plus intraperitoneally (2 cases) with no fetal distress. Although the procedure was uneventful and no clinical evidence of GVHD was observed following delivery, correction of the basic disorders was not accomplished because of anticipated rejection of marrow allografts. We suggest that intrauterine BMT is a relatively simple and safe procedure; once shown to be effective, intrauterine BMT may become the treatment of choice for a large number of patients with life-threatening genetic disorders correctible by BMT during intrauterine life, provided that the procedure can be performed at the earliest possible period of gestation, before development of cell-dependent immune functions.