Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs.
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene on the X-chromosome that result in skeletal and cardiac muscle damage and premature death. Studies in mice, including the mdx mouse model of DMD, have demonstrated that circulating bone marrow-derived cells can participate in skeletal muscle regeneration, but the potential clinical utility of treating human DMD by allogeneic marrow transplantation from a healthy donor remains unknown. To assess whether allogeneic hematopoietic cell transplantation (HCT) provides clinically relevant levels of donor muscle cell contribution in dogs with canine X-linked muscular dystrophy (c-xmd), 7 xmd dogs were given hematopoietic cell (HC) transplants from nonaffected littermates. Compared with the pretransplantation baseline, the number of dystrophin-positive fibers and the amount of wild-type dystrophin RNA did not increase after HCT, with observation periods ranging from 28 to 417 days. Similar results were obtained when the recipient dogs were given granulocyte colony-stimulating factor (G-CSF) after their initial transplantation to mobilize the cells. Despite successful allogeneic HCT and a permissive environment for donor muscle engraftment, there was no detectable contribution of bone marrow-derived cells to either skeletal muscle or muscle precursor cells assayed by clonal analyses at a level of sensitivity that should detect as little as 0.1% donor contribution.
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024, USA.
Chiara
C
Dell'Agnola
Zejing
Z
Wang
Rainer
R
Storb
Stephen J
SJ
Tapscott
Christian S
CS
Kuhr
Stephen D
SD
Hauschka
Richard S
RS
Lee
George E
GE
Sale
Eustacia
E
Zellmer
Serina
S
Gisburne
Janet
J
Bogan
Joe N
JN
Kornegay
Barry J
BJ
Cooper
Theodore A
TA
Gooley
Marie-Térèse
MT
Little
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007165:Immunosuppression Therapy / Q000379:methods; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D016189:Dystrophin