Genetic variant predicts Tysabri failure


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.

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

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

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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