How can you prevent Huntington's disease

Huntington's Disease : How medicine fights the slow death of the brain

Everything has been going normally for thirty or forty years. Then one arm muscle twitches, one leg involuntarily takes a step, the face suddenly grimaces. Slowly the control of one's own body slips away, the feelings become independent, the memory dwindles and gives way to delusions. The personality disappears. Absent-minded, deprived of any control of speech, gestures and facial expressions, weakened by seizures that sometimes last for hours, and hardly capable of such essential movements as swallowing, the patients die after about fifteen to twenty years of martyrdom. The relatives see it and know: this could soon be me.

Huntington's disease (St. Vitus's dance) is a rare nerve disorder. For the families affected, on the other hand, it is omnipresent. The grandfather dies, three of his sons fall ill. Then his daughter is snapped at by a police officer in the street. She should be ashamed of being drunk so early in the morning! For the woman, a world collapses at this moment. She staggered across the intersection and didn't notice anything was wrong. A first sign of the disease.

That was in the 1960s. The woman was the mother of Nancy Wexler. Since then, the scientist from Columbia University in New York has only driven one goal: She wanted certainty, a test. For decades she searched for the genetic cause and gathered 58 international researchers around her. In 1993 the team was able to announce the result: It is a mutation in the Huntington's disease gene on chromosome 4.

In around ten percent of the 30,000 or so patients in Europe, this change occurs spontaneously. In most of them, however, it is inherited from a parent, which inevitably leads to the disease. Because even a healthy version of the gene from the other parent cannot compensate for the defect. Thanks to Wexler, doctors can diagnose it with a genetic test even before the onset of the disease. To this day, the disintegration of the brain cannot be cured or stopped.

The sisters chose uncertainty

Many offspring of HD victims therefore forego the test. They would rather live life than despair of the unstoppable. Nancy Wexler and her sister also decided against it. “Our father said to us: I don't know what to think of the test. It would be tragic to lose you like that, "she told the American radio station NPR. “It hit us like a thunderbolt. We really wanted to know that we didn't have the disease. But what if it does? ”It makes a difference between constantly thinking about HD and knowing its inevitable fate. One of the great success stories of genetic research was no longer worth much for its own life. The sisters chose uncertainty. As a precaution, they remained childless.

This consideration could now change. For the first time, HD sufferers have reason to be hopeful. Since 2015, a total of 46 patients have been treated with an experimental drug (Ionis-HTTRx). Now, in December 2017, the head of the study, Sarah Tabrizi from University College London, told the British press that the results of the novel therapy were better than anything she had hoped for. Even so, it is only a phase I study that was only intended to clarify the safety of the therapy, and although a peer-reviewed publication is still pending for the coming year, Tabrizi says: "For the first time there is the possibility that we will have a therapy that delay or even prevent Huntington's disease. "

In addition to British and Canadians, German patients in particular took part in the study by the Californian biotech company "Ionis Pharmaceuticals" (formerly Isis) and the Swiss pharmaceutical company Roche. "Ulm is the headquarters of the European Huntington's Disease Network," says Bernhard Landwehrmeyer from the Neurology Clinic at Ulm University. Around a third of all patients in Europe would be cared for there. Together with the Bochum University Clinic, the oldest Huntington's disease specialist clinic in Germany, the necessary structures for studies have been created here.

Huntington's disease is the most curable of the incurable neurodegenerative diseases, says the neurologist, who has been looking for Huntington's disease therapy for 15 years. The genetic basis is known very well. The disease occurs because the cell stutters while copying the genetic makeup of the Huntington's disease gene. There is a sequence of three DNA building blocks that most people repeat up to 20 times: CAG, i.e. cytosine, adenine, guanine. The stuttering of the copying mechanism means that there can be more. The disease breaks out after 36 repetitions. The more CAGs, the earlier in life.

Stop the toxic variant of the protein

Because the Huntington's gene is translated into a protein that is important for nerve cells, huntingtin. However, the many CAG repetitions change it so much that the useful protein suddenly becomes toxic. It's too big, lumpy. With devastating consequences in the brain, especially in a region called the striatum. The striatum enables coordinated movements by dampening impulses from other brain regions on the movement centers. In HD patients, the attenuation is lost when these nerve cells die. The muscles twitch involuntarily.

Anyone who wants to cure Huntington's disease must therefore prevent more and more toxic variants of the protein from being formed. As soon as the genetic cause of Huntington's disease was known, researchers suggested stopping the translation of the defective HD gene. They wanted to use “antisense” molecules to intercept copies of the gene, the HD RNA. The antisense molecules are built in such a way that they have a mirror-image sequence of genetic components to the Huntington's RNA. They cling to it. And without RNA, there would be no blueprint for the protein huntingtin.

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