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 nervo us system (CNS) has limited therapeutic efficacy due to the presence of the blood-brain barrier (BBB). We found that three of five rhesus monkeys inje cted 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 autoimmun e encephalomyelitis induced by whole myelin, The intrathecally injected vec tor consistently diffused within the CNS via the cerebrospinal fluid and in fected 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 demyelin ation, necrosis, and axonal loss. The protective effect was associated with ill situ downregulation of inflammatory mediators such as tumor necrosis f actor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1), upr egulation of transforming growth factor beta (TGF-beta), and preservation o f BBB integrity. Our results indicate that intrathecal delivery of HSV-1-de rived vectors containing antiinflammatory cytokine genes may play a major r ole in the future therapeutic armamentarium of inflammatory CNS-confined de myelinating diseases and, in particular, in the most fulminant forms where conventional therapeutic approaches have, so far, failed to achieve a satis factory control of the disease evolution.