Fibroblast growth factor-II gene therapy reverts the clinical course and the pathological signs of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice

Abstract

The development of therapies aimed to promote remyelination is a major issue in chronic inflammatory demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS), where the permanent neurological impairment is due to the axonal loss resulting from recurrent episodes of immune-mediated demyelination. Here, we show that the intrathecal injection of a herpes simplex virus (HSV) type-1 replication-defective multigene vector, engineered with the human fibroblast growth factor (FGF)-II gene

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

“…Studies testing elevated levels of FGF2 indicate a potential mitogenic role of FGF2 signaling, which may be distinct from the response elicited by endogenous FGF2 in lesioned white matter. The number of OP cells and oligodendrocytes increased with FGF2 overexpression from viral transduction early in the course of EAE and this effect was partially abrogated with a second treatment later in EAE disease progression [38]. One possible explanation for the different effects interpreted from FGF2-null mice versus FGF2 overexpression is that supraphysiological elevation of FGF2 levels could result in proliferation that is not stimulated by endogenous FGF2 levels.…”

Vectors for the treatment of autoimmune disease

“…Similarly, fibroblast growth factor-II encoded from HSV reversed disease in a mouse model of EAE. 71 In the mouse STZinduced diabetes model, administration of replicationdefective HSV encoding nerve growth factor reduced the sensory neuropathy observed in this model. 72 …”

Gene therapy in autoimmune, demyelinating disease of the central nervous system

“…Gene therapy has not yet been attempted in MS, but there have been a number of studies in EAE that have invariably shown some level of efficacy at inhibiting the disease (Table 1), although in many cases this has only been an amelioration rather than elimination of disease. As the majority of the CNS is postmitotic, this puts constraints on the nature of the vector that can be used, and to date administration of plasmid DNA, [32][33][34][35][36][37][38][39][40][41] viral infection, [42][43][44][45][46][47][48][49][50][51][52][53] and retrovirally transduced cell (RVC)-carriers 47,[54][55][56][57][58][59][60][61][62][63] have been investigated in EAE (Table 1). These have largely focused on inhibition of the immune response either applied centrally to target the local pathological events within the CNS or peripherally administered to inhibit: initial sensitization, the activities of circulating cells or perivascular events in areas of local BBB breakdown.…”

“…In addition, some studies have attempted to promote repair or inhibition of the demyelination process. 40,44,49,57,61 Cytokines are dynamically expressed as lesions evolve and resolve [12][13][14][15][16] and are of major importance in the development and control of autoimmunity. 12 Many studies in EAE focus on the use of knockout mice.…”

“…102,[104][105][106][107] Although some success has been shown by genedelivered growth factors that provide trophic support (eg NGF and PDGF. Table 1), 49,57 neuroprotection by any route in CNS autoimmunity, particularly in long-established disease, is essentially unexplored. However, there is evidence from other neurodegenerative systems that gene delivery of growth factors can promote remyelination.…”