TY - JOUR
T1 - VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency
AU - Young, Pampee P.
AU - Fantz, Corinne R.
AU - Sands, Mark S.
N1 - Funding Information:
This work was supported in part by Vanderbilt Institutional Funds (P.P.Y.), NIH training grant T32HL07088 (P.P.Y.), NIH grants DK057586 and NS44520 (M.S.S.), and Hunter's Hope Foundation (C.R.F.).
PY - 2004/7
Y1 - 2004/7
N2 - The course of certain congenital neurodegenerative diseases like lysosomal storage diseases (LSDs) begins shortly after birth and can progress quickly. Ideally, therapeutic interventions for LSDs, which include bone marrow transplantation (BMT), recombinant enzyme replacement, or systemic viral-mediated gene therapy, should be initiated at birth. However, the blood-brain barrier (BBB) remains an obstacle to effective therapy even when these strategies are initiated at birth. We studied whether VEGF, an endothelial cell mitogen and permeability factor, can open the BBB in newborn mice for therapeutic purposes. Intravenous (IV) administration of VEGF at birth increased BBB permeability within 2 h. The increased permeability persisted for at least 24 h, became undetectable 48 h after injection, and was restricted to newborns. Systemic VEGF treatment before BMT or administration of recombinant lentivirus resulted in increased numbers of both donor cells and virus-transduced cells, respectively, in the recipient brain. Administration of VEGF before BMT in newborn mice with a neurodegenerative LSD, globoid-cell leukodystrophy, resulted in a significant increase in life span compared to affected animals that were injected with saline before BMT.
AB - The course of certain congenital neurodegenerative diseases like lysosomal storage diseases (LSDs) begins shortly after birth and can progress quickly. Ideally, therapeutic interventions for LSDs, which include bone marrow transplantation (BMT), recombinant enzyme replacement, or systemic viral-mediated gene therapy, should be initiated at birth. However, the blood-brain barrier (BBB) remains an obstacle to effective therapy even when these strategies are initiated at birth. We studied whether VEGF, an endothelial cell mitogen and permeability factor, can open the BBB in newborn mice for therapeutic purposes. Intravenous (IV) administration of VEGF at birth increased BBB permeability within 2 h. The increased permeability persisted for at least 24 h, became undetectable 48 h after injection, and was restricted to newborns. Systemic VEGF treatment before BMT or administration of recombinant lentivirus resulted in increased numbers of both donor cells and virus-transduced cells, respectively, in the recipient brain. Administration of VEGF before BMT in newborn mice with a neurodegenerative LSD, globoid-cell leukodystrophy, resulted in a significant increase in life span compared to affected animals that were injected with saline before BMT.
KW - BMT
KW - Blood-brain barrier
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=2942553230&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2004.03.007
DO - 10.1016/j.expneurol.2004.03.007
M3 - Article
C2 - 15191807
AN - SCOPUS:2942553230
SN - 0014-4886
VL - 188
SP - 104
EP - 114
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -