September 22, 1999
Stem Cells May Be Powerful Gene Shuttle
Stem cells may prove to be a better shuttle than viruses for
delivering corrective genes to tissues throughout the body, say
researchers from the Howard Hughes Medical Institute (HHMI) at
Children's Hospital in Boston and Harvard Medical School.
Stem cells are immature cells that have the unique capacity to give
rise to populations of mature, functioning cells. Using stem cells
derived either from the bone marrow or from specific organs to carry
therapeutic genes back to sites of disease might prove advantageous
because it may "remodel" genetically defective organs and tissues,
allowing them to permanently carry the corrective gene, say HHMI
investigators Richard Mulligan and Louis
Kunkel of Children's Hospital and Harvard Medical School, whose
laboratories collaborated on this study.
Virus-based gene therapies for muscular dystrophy, for example, must
be injected directly into the muscle, and they only correct the altered
tissue locally, said Kunkel. "If the virus doesn't reach stem cells,
the therapeutic effect is lost when the muscle degenerates naturally.
Stem cell therapy has the potential to fundamentally remodel the tissue
itself," said Kunkel, an expert on the molecular basis and treatment of
muscular dystrophies. More importantly, said Mulligan, "the use of stem
cells for transplantation appears to result in the disseminated
delivery of cells, a critical requirement for the effective treatment
of a disease such as muscular dystrophy, where the afflicted cells are
found throughout the body."
In an article in the September 23, 1999, issue of Nature,
Mulligan's and Kunkel's laboratories describe the development and
testing of their approach in a mouse model of the human disease
Duchenne muscular dystrophy (DMD). Like patients with DMD, the mice do
not produce the protein dystrophin, the absence of which causes rapid
and life-threatening deterioration of muscles.
The researchers first irradiated female mice to eliminate any
blood-related, or hematopoietic, stem cells, which are normally found
in bone marrow. The scientists then injected into the female mice,
dystrophin-positive stem cells isolated from the bone marrow or muscle
tissue of male mice.
To their surprise, the scientists found that the injected
hematopoietic stem cells and the muscle stem cells were both able to
give rise to blood cells and also provided for the engraftment of
diseased muscle with healthy muscle cells expressing dystrophin.
While the researchers caution that their results are still
preliminary, their findings hint that adults may harbor stem cells from
a variety of organs and tissues that might be manipulated to heal
genetic defects in organs and tissues throughout the body.
The scientists say, however, that the restorative effects were well
below what would be required if the technique were to be used for
clinical treatment. But they believe there are ways to improve the
method.
The discovery of similarities in hematopoietic and muscle stem cells
also raises important questions about the origin of stem cells and
their therapeutic potential, said Mulligan, an expert in the
development of gene transfer technology and leader of the gene therapy
efforts at Harvard.
"The muscle-derived stem cells might originate from the
hematopoietic compartment or they might be present in muscle as a
consequence of the natural process of development," said Mulligan.
"However, it might make sense for hematopoietic stem cells to
communicate with organs and tissues, since they have the capacity to
traffic throughout the body," he added. "The hematopoietic system might
be able to sense the need for replenishment of cells and organs or
tissues," and provide the cells necessary for tissue or organ
repair.
Mulligan said that it will be important to compare the properties of
the adult stem cells they have isolated to embryonic stem cells, which
are known to be able to give rise to a broad range of tissues.
Embryonic stem cells are now being studied for use in tissue
transplantation
"Perhaps such breadth is not necessary," Mulligan noted. "It might
be that different adult stem cell populations will still have the
capacity to give rise to cells from the organ in which they
originated."
If the existence of organ-specific stem cells is confirmed, and if
researchers can determine the cellular signals that control their
differentiation, it might be possible to use the cells to genetically
"remodel" heart, liver, pancreas or brain tissue, theorize the
scientists. And if hematopoietic stem cells can be manipulated to
produce organ-specific cells, they may one day prove to be a better
source of therapeutic cells than the damaged organs.
Mulligan's and Kunkel's collaborators on the Nature paper
were postdoctoral fellows Emanuela Gussoni and Yuko Soneoka, Corinne
Strickland, Elizabeth Buzney, Mohamed Khan and Alan Flint.
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