Blood, 1 March 2001, Vol. 97, No. 5, pp. 1153-1153
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 
-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 -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.
Charles L. Sawyers
University of California Los Angeles
