Genetic variant predicts Tysabri failure

Rossi S et al. A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation.Mult Scler. 2012 May. [Epub ahead of print]

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation.

Objective: To determine the role of natalizumab-induced lymphocytosis (cell destruction) and of Akt polymorphisms (variants of the gene sequence making variants in the protein) in disease reactivation after natalizumab discontinuation.

Methods: Peripheral leucocyte (white blood cell) count and composition were monitored in 93 MSers during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic (suicide by the cell) pathway and lymphocyte survival is regulated by the apoptotic cascade.

Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation.

Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab

As with all genetic studies that are small scale (e.g. less than two thousand) there are risks of false positive/negative results. These things all need replicating and very seldom do replicate. However, if we did know which people were at risk of developing a post-Tysabri relapse one could perhaps modify treatment options or monitoring, which has to tempered by the risks of PML development.  At some stage everybody will probably end up with their genomes sequenced and if you can use the information wisely, one could work out your pharmacogeneomics, which is how your genetic code can influence drug metabolism. It could help inform drug choices.

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