Gene therapy for chronic relapsing experimental allergic encephalomyelitis using cells expressing a novel soluble p75 dimeric TNF receptor.
In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block TNF was investigated with the use of a retroviral dimeric p75 TNF receptor (dTNFR) construct. To effectively produce these TNF inhibitors in vivo, a conditionally immortalized syngeneic fibroblast line was established, using a temperature-sensitive SV40 large T Ag-expressing retrovirus. These cells were subsequently infected with a retrovirus expressing soluble dTNFR. CNS-injected cells could be detected 3 mo after transplantation and were shown to produce the transgene product by immunocytochemistry and ELISA of tissue fluids. These levels of dTNFR protein were biologically active and could significantly ameliorate both acute and relapsing EAE. This cell-based gene-vector approach is ideal for delivering proteins to the CNS and has particular relevance to the control of inflammatory CNS disease.
Croxford
J L
JL
Neuroinflammation Group, Institute of Neurology, and Department of Clinical Science, Institute of Ophthalmology, University College London, United Kingdom.
Triantaphyllopoulos
K A
KA
Neve
R M
RM
Feldmann
M
M
Chernajovsky
Y
Y
Baker
D
D
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D016380:Brain Tissue Transplantation / Q000276:immunology; D002461:Cell Line, Transformed; D002908:Chronic Disease; D019281:Dimerization; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology; D006801:Humans; D007276:Injections, Intraventricular; D007668:Kidney / Q000166:cytology; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II; D012008:Recurrence; D012995:Solubility
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II