FGFs And The Treatment Of Cns Injuries

The data presented so far show that members of the FGF family are promising candidates for the treatment of nerve injury or disorder. Different ways of using FGFs as therapeutics can be suggested. With regard to the application mode, recent studies suggest to use genetically modified cells for FGF supply rather than to inject or infuse FGF directly.

An approach which might be convenient for a wide spectrum of nerve injuries is the so-called cell replacement or cell recruitment strategy. The recent demonstration of plasticity in neural progenitor cells when transplanted to different regions raises the hope that immature neurons generated from cultured stem cells could replace a variety of neuronal subtypes.158-160 However, currently only a few studies have examined the fate and the effects of FGF-2- or EGF-expanded progenitor cells after transplantation in the CNS.126 Another promising attempt with regard to the expansion of neuronal progenitor cells has been demonstrated using EGF. In vivo infusion of EGF into the adult mouse forebrain which contains both neuronal stem and progenitor cells, results in a dramatic increase in the proliferation and the total number of subependymal cells and induced their migration away from the lateral ventricle into adjacent parenchyma.161

Another possible way to take advantage of the neurotrophic capacities of FGF-2 is in the context of neural transplantation. The clinical use of fetal nigral and adrenal medullary grafts as an intracerebral source of dopamine in patients with Parkinson's disease is limited, at least in part, because of the poor survival of the donor tissue.162163 Enhancement of the graft survival can be achieved by co-grafting of fetal dopaminergic neurons with a FGF-2 source like, for example, genetically modified cells which produce FGF-2.164 In addition, in viro propagation of fetal precursor cells before transplantation leads to a long-term survival of the graft.165 Alternative gene delivery techniques include the use of viral vectors and the ex vivo technology.166 The ex vivo approach allows manipulation of the cells in culture for reimplantation after isolation from the patient.

FGF-2, the most promising candidate of the FGF family, occurs in different isoforms. However, all of the effects of FGF-2 reported so far have been achieved by application of the 18-kDa isoform. It is therefore not clear whether all isoforms display similar activities or whether they differentially regulate cell metabolism. A correlation between expression of a certain isoform and cell morphology has been demonstrated, for example, in cardiac myocytes.69 In the peripheral nervous system, FGF-2 isoforms were found to be differentially regulated in spinal ganglia and at the lesion site after sciatic nerve injury.167 This differential regulation might be evidence for an isoform-specific function. Analysis of the FGF-2 isoform effects may therefore lead to therapeutic tools with increased efficiency and specificity and, possibly, less side effects. The same is true for the recently identified FHFs, which are also present in the nervous system.

In addition to the neurotrophic activities of FGFs which could be exploited for treatment strategies of the injured CNS, the involvement of FGFs in tumor growth might be also relevant. FGF-2 seems to be a key molecule in glial tumorigenesis.168

In vitro studies have shown that glioma cell growth is inhibited after application of FGF-2 antisense oligonucleotides.168-171 Although, the therapeutic application of antisense oligonucleotides is still in an experimental stage,172 the in vivo administration of FGF-2 antisense probes could be a promising strategy in CNS tumor treatment.173

In conclusion, treatment of neuronal precursor cells with FGF-2 and co-grafting of a FGF-2 source with specific embryonic neuronal subpopulations seem to be promising therapeutical strategies for the injured CNS. Analysis of the neurotrophic capacities of the higher molecular weight FGF-2 isoforms and of the FHFs could provide a more effective FGF molecule for injured central neurons.

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