Treating nonhematologic disorders with hematologic stem cells: can this work?

Two articles in this issue address the utility of hematologic stem cell transplantation for the treatment of nonhematologic inherited diseases. The premise is that genetic deficiencies in nonhematologic tissues can be corrected by allogeneic transplantation of hematopoietic stem cells from healthy sibling donors. Why should this work? In some cases, the affected tissue is derived from mesenchymal progenitor cells, which are present in bone marrow and can be transplanted and expanded in the host. In other situations, the disease is caused by mutation in a broadly expressed, secreted enzyme that can be replaced exogenously in the form of protein therapy or by allogeneic transplantation of enzyme-secreting hematopoietic stem cells. In both examples, corrective measures must be undertaken early to prevent irreversible tissue damage.

Horwitz et al (page 1227) describe the clinical outcome of three children with osteogenesis imperfecta (OI) treated by allogeneic bone marrow transplantation (BMT). OI is an autosomal-dominant genetic disorder caused by defective production of type I collagen, leading to numerous skeletal defects and short stature. In an earlier report, this group demonstrated that donor-derived osteoblasts could be isolated from 2 children who received allotransplants for OI, providing evidence for engraftment of donor-derived mesenchymal cells after BMT. Here we learn that these children and an additional patient show increased bone mineral content and body length. These effects were observed primarily in the first 3 to 6 months after transplantation, but bone mineral content continued to increase for the duration of the 18-36–month follow-up. Remarkably, these improvements in bone growth occurred with apparently low levels of donor osteoblast engraftment (in the 1.5-2.0 percent range).

Soper et al (page 1498) tackle a complementary issue using a mouse model of β-glucuronidase deficiency, a lysosomal storage disorder analogous to Sly disease in humans. As with OI, successful treatment requires intervention in infancy to avoid irreversible damage to the heart, liver, nervous tissue, and other organs. Currently, this is accomplished using myeloablative conditioning regimens followed by allogeneic BMT. Because the toxicities of conditioning chemotherapy are significant, there is concern about treatment-related side effects. Remarkably, Soper et al demonstrate long-term engraftment of congenic normal murine bone marrow into neonatal mice with β-glucuronidase deficiency in the absence of any conditioning chemotherapy or radiation. This success was possible through the use of very high doses of donor bone marrow cells and led to significant clinical improvement in the mice.

What does the future hold? It seems clear that less toxic preparative regimens can be designed and implemented without compromising engraftment. The 2 to 3 log increase in bone marrow cell dose used by Soper et al presents challenges for implementation in humans, but one can envision the use of selected populations such as cord blood as well as stem cells following ex vivo expansion. An encouraging lesson from both studies is that low levels of engraftment (2 percent and 15 percent, respectively) led to successful treatment of both genetic deficiencies. This success is probably explained by selective retention of the wild-type protein, however, and may not apply generally.