IFN-beta gene transfer into the central nervous system using bone marrow cells as a delivery system.
The peripheral delivery of interferon-beta (IFN-beta) for the treatment of central nervous system (CNS) diseases is only partially effective because of the blood-brain barrier (BBB). To circumvent this problem, we evaluated the feasibility of genetically altering bone marrow cells ex vivo and using them as vehicles to transfer the IFN-beta cDNA into the mouse CNS. An IFN-beta retroviral expression vector (pLXSN-IFNbeta) was used to stably transfect PA317 cells. The supernatant from these producer cells, which expressed IFN-beta mRNA and protein, were used to infect bone marrow cells. When transplanted into irradiated mice, IFN-beta-engineered marrow cells accessed the CNS and expressed IFN-beta mRNA and protein. Marrow cells transduced with a control neomycin vector entered the brain and expressed the neomycin but not the IFN-beta gene. In the CNS, IFN-beta delivered by marrow cells induced the mRNA expression of 2',5'-oligoadenylate synthetase (2',5'-OAS), indicating biologic activity. Our findings demonstrating that bone marrow cells can serve as a delivery system for IFN-beta cDNA into the CNS could have implications for the treatment of neurologic disorders, such as multiple sclerosis (MS), viral encephalitis, and brain tumors.
Department of Neurology, University of Maryland, and Department of Veterans Affairs, Baltimore, MD 21201, USA.
Tapas Kumar
TK
Makar
Susan
S
Wilt
Zhongyun
Z
Dong
Paul
P
Fishman
M Maral
MM
Mouradian
Suhayl
S
Dhib-Jalbut
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004790:Enzyme Induction; D005240:Feasibility Studies; D017930:Genes, Reporter; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000493:pharmacokinetics*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D019868:Kanamycin Kinase / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013047:Specific Pathogen-Free Organisms; D014162:Transfection
D018076:DNA, Complementary; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016899:Interferon-beta; D019868:Kanamycin Kinase; D015088:2',5'-Oligoadenylate Synthetase