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Towards a treatment for Huntington's: two small molecules may revolutionize the treatment of an incurable disease

Weizmann Institute scientists have shown in a mouse model that the drugs succeed in penetrating through the blood-brain barrier, delaying the progression of the disease and even reversing it

The human brain is a well-secured control cell whose roads leading to it - the blood vessel system in the brain - are surrounded by a tight barrier of dense cells that limit the entry and exit of substances. This fortified architecture protects the brain, but may also keep help away from it when needed, for example when a neurodegenerative disease develops. In a new study, which is published in the scientific journal EMBO Molecular Medicine, Prof. Gilo Rebecca Dickstein and her group from the Weizmann Institute of Science two small molecules that manage to penetrate through the blood-brain barrier and lower the levels of the protein that causes an incurable neurodegenerative disease known as Huntington's. The new drugs delayed the progression of the disease in a mouse model and even reversed it. 

Personalized medicine. The image was prepared with the help of DALEE artificial intelligence software and is not a scientific image
Personalized medicine. The image was prepared with the help of DALEE artificial intelligence software and is not a scientific image

Huntington's disease usually starts around the age of 40, and is first felt by slight involuntary movements, general clumsiness and increased anxiety. The disease, which develops over years and eventually leads to death, is caused by the over-duplication of a certain DNA segment in the huntingtin gene, so that it is repeated 36 times or more. Patients usually have one normal copy of the gene and one defective one, whose expression leads to the creation of defective proteins that stick to each other and become a toxic deposit in the brain. The sediment accumulates and causes a lot of damage in a variety of ways - from the development of inflammation, through damage to the expression of genes important for the survival of nerve cells, to damage to the cell's power plants (mitochondria). Previous attempts to treat each mechanism separately were not effective enough, and drugs that have been tried in recent years and aimed at the root of the problem - the defective huntingtin protein - had difficulty separating it from the normal proteins. 

A clue to the solution of the problem was found by Dr. Anat Bhatt, a scientist from Prof. Dickstein's group in the Department of Biomolecular Sciences at the institute, already in 2019. The group has been researching for many years and at the basic level a control protein called Spt5 that helps in the production process of messenger RNA molecules and is especially required to create proteins involved in inflammatory conditions. Spt5 is a large protein with many binding sites, and the scientists discovered at the time that small molecules could block selected functions of it without actually harming other functions. This is how they discovered three small molecules that block the production of damaged huntingtin, without significantly affecting the production of normal huntingtin and other proteins involved in inflammatory conditions.

In the new study, the team of researchers led by Dr. Bhatt tested 17 molecules whose chemical structure is similar to those found to be effective in the previous study, in order to locate the most effective inhibitors of defective huntingtin production. Using cell cultures from a mouse model of Huntington's disease, two small molecules were discovered to be the most effective. The new molecules were then tested in cell cultures from human patients with different degrees of severity of the genetic defect and a significant decrease in the amount of the defective protein was detected in each of the cases. Also, no corresponding decrease in the amount of the normal protein was detected - evidence of the precise action of the new molecules. 

In the next step, the two selected molecules were tested in vivo in a genetically modified mouse model expressing a defective full-length human huntingtin gene. First, the mice received the treatment at an advanced age after they had already shown clear signs of the disease, through a direct infusion into the damaged area of ​​the brain for four weeks. The treatment was able to lower the expression of the defective gene copy and increase the proportion of normal proteins out of all huntingtin proteins in the damaged area of ​​the brain. 

Also, the treatment was able to repair some of the damage of the disease: it increased the expression of two genes that are usually affected as the disease progresses, one is a growth factor essential for the survival of nerve cells and the other belongs to the cellular powerhouses. "Even though the adult mouse model simulated a disease in an advanced stage," explains Dr. Bhatt. "The treatment managed to turn the wheel back. We identified in behavioral tests that the level of anxiety decreased and there was an improvement in coordination and balance." 

However, administering a drug by direct infusion to the damaged area of ​​the brain requires a complex medical procedure involving risks and pain for the patients. Therefore, the scientists turned to check whether the drugs are effective even when they are given daily orally or by subcutaneous injection. The team was excited to discover that these methods of taking the drug also led to a decrease in the levels of defective huntingtin in the mice's brains and found that the molecules manage to complete the long journey from the mouth or skin to the brain without undergoing a significant change. When reaching the destination, their properties allow them to pass the blood-brain barrier and enter directly into the focus of the problem. 

One of the small molecules showed a curative effect at extremely low doses - an important feature for a drug intended for use in humans - but its drawback was that it affected more than 1,000 additional genes. The second molecule required treatment at higher doses, but proved to be a fairly precise weapon that lowered the expression of the defective gene without causing widespread effects on other genes or side effects. 

In the last part of the experiment, the effect of the new treatment was tested when it was given for two months orally, at an early stage when the initial symptoms are just beginning to develop. All the sick mice showed increased anxiety even before the start of the experiment, but in the treated mice it returned to a healthy level. Over time, the loss of balance and the hyperactive behavior of the diseased mice worsened, while in the treated mice the balance was less damaged and the worsening of the hyperactivity was prevented. These findings and other tests carried out indicated that the new drugs delay the progression of the disease even when given at an early stage. 

"We were happy to find out that the small molecules were able to reach the brain without changing or breaking down on the way," says Prof. Dickstein. "While other experimental treatments involve repeated brain or spinal surgeries, the small molecules may allow effective and safe treatment of Huntington's given orally or by subcutaneous injection. In recent years, the understanding that small molecules can be used to attack a specific function of large control proteins in a targeted manner, without harming their overall activity, has been taking shape. This understanding may lay the foundations for new treatments for a variety of diseases." 

Elad Itzhaki and Dr. Benjamin Weiss from the Department of Biomolecular Sciences at the Institute also participated in the study; Dr. Michael Tolmsov from the Department of Life Sciences and the Multidisciplinary Center for Brain Research at Bar Ilan University; Dr. Michael Tzuri from the Department of Veterinary Resources at the Institute; Dr. Alexander Brandis from the Department of Life Sciences Research Infrastructures at the Institute; and Dr. Christo Shorush from the Medicinal Chemistry Unit at the Israeli National Center for Personalized Medicine at the institute.

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