Un fattore di rischio genetico potrebbe spiegare gli effetti dannosi dei farmaci sui pazienti affetti da sclerosi multipla
Articolo dell'11 luglio 2012:
Un gruppo coordinato dal neuroimmunologo Lars Fugger, dell'Università di Oxford, riporta che una variazione legata alla SM nella sequenza dei geni relativi al recettore FTN alfa potrebbe aiutare a spiegare, e perfino a prevedere, un risultato negativo nel paziente con SM di un farmaco contenente un bloccante del FTN alfa. Ciò costituisce anche un esempio di come alcuni piccoli segnali genetici analoghi possano essere utilizzati a scopi clinici. Trevor Kilpatrick, neurologo all'Istituto Florey per le Neuroscienze dell'Università di Melbourne, sottolinea l'importanza del lavoro e afferma che fornisce un ponte interessante tra le piccole differenze nella sequenza genetica e il funzionamento delle proteine che ne risultano. I ricercatori forniscono anche evidenze riguardo le sfumature specifiche di una patologia, cioè su come viene regolato il sistema autoimmunitario, sottolineando l'importanza di questi scambi delle sequenze sulle singole unità nel determinare la suscettibilità delle persone ad ammalarsi di patologie gravi come la sclerosi multipla. Questa osservazione è emersa da uno studio che ha identificato sostituzioni di una lettera, fenomento conosciuto come polimorfismi del nucleotide singolo, legate statisticamente ad un rischio maggiormente elevato di ammalarsi di SM. Interessante notare che questi polimorfismi si trovano nel gene del recettore del FTN alfa. Il legame tra SM e FTN alfa ha portato i ricercatori ad investigare il percorso della proteina che risulta dal polimorfismo del singolo nucleotide. Il nucleotide singolo produce una versione ridotta del recettore. Sebbene questa molecola si unisca comunque al FTN alfa, i segmenti mancanti gli impediscono di entrare nella membrana plasmatica. Piuttosto, la forma alternativa permane a girare intorno la cellula, legandosi al FTN alfa e rallentando l'attività di quest ultimo (quindi l'opposto funzionamento della forma completa). Così facendo, il recettore ridotto tiene il FTN alfa lontano dal suo posto naturale sulla superfice cellulare. I ricercatori suggeriscono che questo funzionamento di bloccaggio del FTN alfa rispecchia l'attività clinica degli antagonisti del FTN alfa, che può esacerbare la sclerosi multipla. La scoperta indica che il blocco del FTN aumenta i rischi nella SM, e che determinati farmaci possono amplificare questo effetto. Inoltre, comprendere il funzionamento di questo recettore ridotto potrebbe aiutare a prevedere gli effetti collaterali di questo tipo di farmaci sul paziente già nei trials clinici. Se i ricercatori avessero saputo della correlazione tra la patologia e la firma genetica che interferisce con l'attività del FTN alfa, essi avrebbero potuto prevedere che bloccare il FTN alfa con i farmaci avrebbe potuto dare vita a problemi. Il genotipo potrebbe costituire una via d'accesso alla comprensione del funzionamento dei farmaci e sul perchè gli effetti sono così differenti di persona in persona. Adesso la ricerca deve concentrarsi sul capire perchè questi polimorfismi sono collegati alla patologia.
Fonte: http://www.sclerosimultipla.com/news/vars/n/un-fattore-di-rischio-genetico-potrebbe-spiegare-gli-effetti-dannosi-dei-farmaci-sui-pazienti-affetti-da-sclerosi-multipla/64
In the human genome is a single letter that could reveal genetic therapy designed to slow because multiple sclerosis, often ends up worsening the clinical picture. New research reveals that there is little genetic variation, which, combined with a small increased risk of MS, inhibits the activity of tumor necrosis factor alpha, a key regulator of the immune system. The discovery could explain how the drugs that have an interference with this protein, they end up exacerbating the SM. FTN alpha inhibitors are often included in the drugs for autoimmune diseases. However, when the researchers tested anti FTN alpha therapy in MS patients, the drugs have caused a worsening of the disease in different subjects.
A group, led by Lars Fugger neuroimmunologo, University of Oxford, shows that a variation linked to MS in the sequence of genes related receptor alpha FTN may help to explain, and even to predict a negative outcome in patients with MS of a drug containing an alpha blocker FTN. This is also an example of how some small genetic signals analogues could be used for clinical purposes. Trevor Kilpatrick, a neurologist Florey Institute for Neurosciences, University of Melbourne, emphasizes the importance of work and says it provides an interesting bridge between small differences in the genetic sequence and function of proteins that result. The researchers also provide evidence about the nuances of a specific disease, that is how you adjust the auto-immune system, emphasizing the importance of these exchanges of sequences of individual units to determine the susceptibility of people to fall ill with serious diseases such as multiple sclerosis. This observation has emerged from a study that identified a letter substitutions, fenomento known as single nucleotide polymorphisms, linked to a statistically higher risk of developing MS. Interestingly, these polymorphisms are found in the receptor gene alpha FTN. The link between MS and alpha FTN has led researchers to investigate the location of the protein that results from single nucleotide polymorphism. The single nucleotide produces a smaller version of the receptor. Although this molecule is joining to the FTN alpha however, the missing segments prevent it from entering the plasma membrane. Rather, the alternative form continues to revolve around the cell, binding to FTN alpha and slowing down the activity of this last (and then the reverse operation of the full form). In doing so, the reduced receptor alpha FTN keeps away from its natural place on the cell surface. The researchers suggest that this operation locking FTN alpha reflects the clinical activity of alpha antagonists FTN, which can exacerbate multiple sclerosis. The finding indicates that blockade of FTN increases the risk of MS, and that certain drugs may amplify this effect. Moreover, understanding the functioning of this receptor may help predict reduced the side effects of these drugs on patients already in clinical trials. If the researchers had known of the correlation between the disease and the genetic signature that interferes with the activity of alpha FTN, they would have predicted that block alpha with FTN drugs could give rise to problems. The genotype could be a gateway to understanding the operation of drugs and why the effects are so different from person to person. Now the search should focus on understanding why these polymorphisms are related to disease.
In the human genome is a single letter that could reveal genetic therapy designed to slow because multiple sclerosis, often ends up worsening the clinical picture. New research reveals that there is little genetic variation, which, combined with a small increased risk of MS, inhibits the activity of tumor necrosis factor alpha, a key regulator of the immune system. The discovery could explain how the drugs that have an interference with this protein, they end up exacerbating the SM. FTN alpha inhibitors are often included in the drugs for autoimmune diseases. However, when the researchers tested anti FTN alpha therapy in MS patients, the drugs have caused a worsening of the disease in different subjects.
A group, led by Lars Fugger neuroimmunologo, University of Oxford, shows that a variation linked to MS in the sequence of genes related receptor alpha FTN may help to explain, and even to predict a negative outcome in patients with MS of a drug containing an alpha blocker FTN. This is also an example of how some small genetic signals analogues could be used for clinical purposes. Trevor Kilpatrick, a neurologist Florey Institute for Neurosciences, University of Melbourne, emphasizes the importance of work and says it provides an interesting bridge between small differences in the genetic sequence and function of proteins that result. The researchers also provide evidence about the nuances of a specific disease, that is how you adjust the auto-immune system, emphasizing the importance of these exchanges of sequences of individual units to determine the susceptibility of people to fall ill with serious diseases such as multiple sclerosis. This observation has emerged from a study that identified a letter substitutions, fenomento known as single nucleotide polymorphisms, linked to a statistically higher risk of developing MS. Interestingly, these polymorphisms are found in the receptor gene alpha FTN. The link between MS and alpha FTN has led researchers to investigate the location of the protein that results from single nucleotide polymorphism. The single nucleotide produces a smaller version of the receptor. Although this molecule is joining to the FTN alpha however, the missing segments prevent it from entering the plasma membrane. Rather, the alternative form continues to revolve around the cell, binding to FTN alpha and slowing down the activity of this last (and then the reverse operation of the full form). In doing so, the reduced receptor alpha FTN keeps away from its natural place on the cell surface. The researchers suggest that this operation locking FTN alpha reflects the clinical activity of alpha antagonists FTN, which can exacerbate multiple sclerosis. The finding indicates that blockade of FTN increases the risk of MS, and that certain drugs may amplify this effect. Moreover, understanding the functioning of this receptor may help predict reduced the side effects of these drugs on patients already in clinical trials. If the researchers had known of the correlation between the disease and the genetic signature that interferes with the activity of alpha FTN, they would have predicted that block alpha with FTN drugs could give rise to problems. The genotype could be a gateway to understanding the operation of drugs and why the effects are so different from person to person. Now the search should focus on understanding why these polymorphisms are related to disease.
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