Localized over expression of FGF9 in the rat motor cortex reproduces the pathological features of grey matter lesions in progressive multiple sclerosis. (P2.364)

Objective: To investigate the role of fibroblast growth factor 9 (FGF9) in the development of grey matter lesions in multiple sclerosis. Background: Building on data demonstrating FGF9 inhibits remyelination and induces a pro-inflammatory signalling environment in vitro , we proposed its expression at sites of ongoing tissue damage in patients with progressive disease exacerbates axonal injury and loss. We have now tested this hypothesis in vivo. Design/Methods: The pathophysiological consequences of increasing availability of FGF9 in the adult rat motor cortex was investigated using adeno-associated viral vectors encoding FGF9 (AAV-FGF9) and as a control, EGFP (EGFP-AAV). Tissue was harvested 10, 30, 90, 180 and 270 days after stereotactic injection of AVV-FGF9, AAV-EGFP or phosphate buffered saline iand processed for immunocytochemistry, electron microscopy and transcriptional profiling. Results: Stereotactic injection of AAV-FGF9 induced the development of well-demarcated demyelinated lesions in the absence of significant T cell recruitment from the periphery. These cortical lesions were associated with astrocyte hypertrophy, microglial activation and axonal injury/loss, recapitulating the gross pathology associated with many grey matter lesions in progressive multiple sclerosis. However, although demyelination reached a plateau at three months, axonal injury/loss continued to accumulate for the rest of the study. This identified an unexpected detrimental effect of FGF9 signalling on axonal integrity which in vitro transcriptional profiling studies suggest reflects effects due to down regulation of genes encoding neurofilaments and other components of the axonal cytoskeleton. Conclusions: Increasing availability of FGF9 in the rat cortex results in demyelinated lesions that recapitulate the major pathological features associated with grey matter lesions in progressive multiple sclerosis. This observation combined with data demonstrating FGF9 expression is increased in patients identifies FGF9-dependent responses as a logical target for therapies designed to reduce accumulation of disability in patients with progressive disease. Study Supported by: Funding for this study was provided by the Hertie Foundation, Multiple Sclerosis Society and the Naomi Bramson Trust. Disclosure: Dr. Wrzos has nothing to disclose. Dr. McElroy has nothing to disclose. Dr. Thuemmler has nothing to disclose. Dr. Sebastian has nothing to disclose. Dr. Junker has nothing to disclose. Dr. Stadelmann-Nessler has nothing to disclose. Dr. Linington has nothing to disclose.