Di Pardo A, Amico E, Favellato M, Castrataro R, Fucile S, Squitieri F, Maglione V. FTY720 (Fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington Disease. Hum Mol Genet. 2013 Dec [Epub]
Huntington Disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in-vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved motor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect of FTY720 administration was associated with a significant strengthening of neuronal activity and connectivity and, with reduction of mutant huntingtin aggregates and it was also paralleled by increased phosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate protein toxicity.
Huntingtons Disease is a autosomal dominant neurodegenerative disease, that could probably be eliminated by genetic counselling and in vitro fertilization, caused by variant of the huntingtin protein. Can study of HD help unravel effects in MS?
Gilenya modulates both S1P1 and S1P5 receptors. The immune modulating effects are mediated by loss of S1P1 receptors on white blood cells, blocking there path into the block. However the makers of the drug have but great store in the neurological benefits, particularly in S1P5 receptors and have claimers myelin and neuroprotective effects of the drug and have initiated trials in MS.
However in EAE models fingolimod is of course neuroprotective because it is immunosuppressive and the majority of studies show it does little else than blocking the immune system in the periphery and the nerve and myelin saving aspect is not that compelling. Rival companies have questioned the remyelination potential and our own work in non-relapsing secondary progressive EAE did not find evidence to suggest it will work in progressive MS. However we did find much earlier in the disease course that some motor outcomes that we associate with an indicator of nerve loss actually improved with time. Was this plasticity?
However it is interesting that in a model of Huntingtons Disease, where white blood cells are not major players in the neurodegeneration, shows that there is some delay in the demise of the affected mice possibly suggesting some neuroprotective effect of fingolimod and there was maybe some plasticity. So lets hope my fears of failure are unfounded and that Fingolimod will actually work for the non-relapsing progressive MSers and slow progression (although the survival time of the mice was only extended by a few days to a couple of weeks). Of course I expect the relapsing gadolinium enhancing MSers to gain benefit. However who cares what happens in mice..it’s what happens in people that is important.