Delivery to the central nervous system of a nonreplicative herpes simplex type 1 vector engineered with the interleukin 4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis.
Systemic administration of antiinflammatory molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS) has limited therapeutic efficacy due to the presence of the blood-brain barrier (BBB). We found that three of five rhesus monkeys injected intrathecally with a replication-defective herpes simplex virus (HSV) type 1-derived vector engineered with the human interleukin 4 (IL-4) gene were protected from an hyperacute and lethal form of experimental autoimmune encephalomyelitis induced by whole myelin. The intrathecally injected vector consistently diffused within the CNS via the cerebrospinal fluid and infected ependymal cells, which in turn sustained in situ production of IL-4 without overt immunological or toxic side effects. In EAE-protected monkeys, IL-4-gene therapy significantly decreased the number of brain as well as spinal cord inflammatory perivenular infiltrates and the extent of demyelination, necrosis, and axonal loss. The protective effect was associated with in situ downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1), upregulation of transforming growth factor beta (TGF-beta), and preservation of BBB integrity. Our results indicate that intrathecal delivery of HSV-1-derived vectors containing antiinflammatory cytokine genes may play a major role in the future therapeutic armamentarium of inflammatory CNS-confined demyelinating diseases and, in particular, in the most fulminant forms where conventional therapeutic approaches have, so far, failed to achieve a satisfactory control of the disease evolution.
Poliani
P L
PL
Department of Neuroscience, San Raffaele Scientific Institute-DIBIT, 20132 Milan, Italy.
Brok
H
H
Furlan
R
R
Ruffini
F
F
Bergami
A
A
Desina
G
G
Marconi
P C
PC
Rovaris
M
M
Uccelli
A
A
Glorioso
J C
JC
Penna
G
G
Adorini
L
L
Comi
G
G
't Hart
B
B
Martino
G
G
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000517:prevention & control; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D002455:Cell Division; D002490:Central Nervous System / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D004679:Encephalomyelitis / Q000235:genetics* / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D018932:Chemokine CCL2; D016207:Cytokines; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4