title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. pampee.young@vanderbilt.edu
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
authors.forename: Corinne R
authors.initials: CR
authors.lastname: Fantz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods*; D002452:Cell Count; D004195:Disease Models, Animal; D005070:Evans Blue / Q000493:pharmacokinetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007275:Injections, Intravenous; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015996:Survival Rate; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D005070:Evans Blue