Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy.

Pediatr Res 2002 Jan;51(1):40-7

Department of Molecular and Integrative Physiology and the Mental Retardation and Human Development Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

Globoid cell leukodystrophy is an autosomal recessive disease with progressive demyelination caused by a deficiency of the lysosomal enzyme galactosylceramidase. Bone marrow transplantation (BMT) is a therapeutic option for patients with late-onset disease and for patients with early onset disease that had an early diagnosis owing to an affected sibling. This therapy, however, typically is not effective for early onset disease when the diagnosis occurs after several months of life. In an effort to enable a broader range of patients to benefit from BMT, we tested whether combining substrate-reduction therapy with BMT would result in a greater benefit than either treatment alone in the twitcher mouse model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine, an inhibitor of 3-ketodyhydrosphingosine synthase, and transplanted with 50 +/- 5 x 10(6) bone marrow cells on d 10 had a mean life-span of 112 d compared with 51 d for BMT alone (p < 0.001) or L-cycloserine alone, which was previously reported to be 56 d. L-Cycloserine treatment also was initiated neonatally to determine whether it would allow for a delayed BMT to have therapeutic value. Twitcher mice given only BMT at 18 d or only a short course of L-cycloserine died at 36 and 37 d, respectively. Twitcher mice given a short course of L-cycloserine + BMT at 18 d lived to 58 d (p = 0.0006). In conclusion, substrate-reduction therapy enhanced the value of BMT in twitcher mice, suggesting that this combination strategy might benefit patients with globoid cell leukodystrophy.

Download full-text PDF

Source
http://dx.doi.org/10.1203/00006450-200201000-00009DOI Listing
January 2002
4 Reads

Publication Analysis

Top Keywords

cell leukodystrophy
16
globoid cell
16
twitcher mice
16
bone marrow
12
substrate-reduction therapy
12
short course
8
marrow transplantation
8
bmt therapeutic
8
bmt
8
onset disease
8
course l-cycloserine
8
early onset
8
l-cycloserine
5
mice
5
twitcher
5
treatment twitcher
4
therapy bmt
4
combining substrate-reduction
4
tested combining
4
benefit treatment
4

References

(Supplied by CrossRef)

Chen YQ et al.
Hum Mol Genet 1993

Miyataki T et al.
Biochem Biophys Res Commun 1972

Igisu H et al.
Lipids 1988

Vartanian T et al.
Glia 1989

Tapasi S et al.
Indian J Biochem Biophys 1998

Svennerholm L et al.
Prog Clin Biol Res 1982

Bullard W et al.
J Nerv Ment Dis 1906

Krabbe K et al.
Brain 1916

Wenger DA et al.
Mol Genet Metab 2000

De Gasperi R et al.
Hum Mutat 1999

Similar Publications