In utero transplantation of monocytic cells in cats with alpha-mannosidosis.
BACKGROUND
Lysosomal storage diseases are devastating illnesses, in large part because of their neurologic consequences. Because significant morbidity occurs prenatally, in utero (IU) therapy is an attractive therapeutic approach.


METHODS
We studied the feasibility and efficacy of IU injections of monocytic cells (derived from normal marrow) in feline alpha-mannosidosis. Heterozygous cats were interbred to produce affected (homozygous) and control (heterozygous and wild-type) offspring. Thirty-seven pregnancies were studied in which fetuses were transplanted intraperitoneally (1x10 cells/kg recipient) at gestational days 27 to 33 and then each week for 2 weeks (term=63 days). After birth, affected kittens were evaluated clinically and pathologically, tissue alpha-mannosidase levels were assayed, and in many studies, the numbers of alpha-mannosidase-containing cells were enumerated. When male donor cells were transplanted into female recipients, engraftment was also quantified using polymerase chain reaction to amplify a Y chromosome-specific sequence.


RESULTS
We establish methods to transplant cats intraperitoneally while IU using ultrasound guidance, thus, describing a new large animal model for prenatal therapy. We show that the donor monocytic cells engraft and persist (for up to 125 days) in the brain, liver, and spleen, albeit at levels below those needed to alter the clinical or pathological progression of the alpha-mannosidosis.


CONCLUSIONS
This is the first study of monocyte transplantation in a large animal model of a lysosomal storage disorder and demonstrates its feasibility, safety, and promise. Delivering cells IU may be a useful strategy to prevent morbidities before a definitive therapy, such as hematopoietic stem-cell transplantation, can be administered after birth.
Abkowitz
Janis L
JL
Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA. janabk@u.washington.edu
Sabo
Kathleen M
KM
Yang
Zhantao
Z
Vite
Charles H
CH
Shields
Laurence E
LE
Haskins
Mark E
ME
D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D001921:Brain / Q000201:enzymology; D002415:Cats; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D005865:Gestational Age; D007274:Injections, Intraperitoneal; D008099:Liver / Q000201:enzymology; D008297:Male; D009000:Monocytes / Q000637:transplantation*; D011247:Pregnancy; D013154:Spleen / Q000201:enzymology; D013997:Time Factors; D018084:Ultrasonography, Interventional; D014599:Uterus / Q000000981:diagnostic imaging / Q000601:surgery*; D043323:alpha-Mannosidase / Q000378:metabolism; D008363:alpha-Mannosidosis / Q000196:embryology / Q000201:enzymology / Q000601:surgery*
D043323:alpha-Mannosidase