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A platform for the development of accessible drugs for rare genetic metabolic diseases

Researchers at Tel Aviv University developed the platform based on a yeast model, which has a high genetic similarity to humans. The article was published in January 2019 in the journal Nature Communications

The research team at the Blavatnik Center for Drug Development at Tel Aviv University. From right to left - Dr. Edi Fitchenuk, Dr. Dana Laur, Dr. Hamotel Engel and Dr. Avi Reva. Photo: Abashidze Anastasiam
The research team at the Blavatnik Center for Drug Development at Tel Aviv University. From right to left - Dr. Edi Fitchenuk, Dr. Dana Laur, Dr. Hamotel Engel and Dr. Avi Reva.
Photo: Abashidze Anastasiam

Researchers in the laboratory of Prof. Ehud Gazit in the Department of Molecular Microbiology and Biotechnology in the Faculty of Life Sciences at Tel Aviv University have developed an innovative research platform, based on a model of single-celled organisms of the yeast type. The purpose of the system is to investigate the mechanisms of hereditary metabolic diseases, including: phenylketonuria, tyrosinemia, maple syrup disease - MSUD, homocystinuria, and more, and to develop drugs for them. In the absence of treatment, these diseases cause very serious symptoms - such as multi-system damage, neurological deterioration, seizures, intellectual disability and sometimes even autism. The main treatment known today is a severe diet, which is very difficult to adhere to, for life.

The researchers found that the main causes of damage are toxic amyloid structures that form in the cells, of the type also known from severe neurological diseases, such as Alzheimer's and Parkinson's. They also discovered that treatment using well-known amyloid inhibitors such as tannic acid, a natural substance extracted from plants, can prevent the formation of the amyloid structures in the yeast cells and the death of the cells. Following the encouraging findings, the researchers believe that their work may serve as a basis for the development of effective and accessible drugs for severe genetic diseases.
The research was led by Dr. Dana Laor from Prof. Gazit's laboratory, in collaboration with the Blavatnik Center for Drug Development at Tel Aviv University. The article was published in January 2019 in the journal Nature Communications.

"Amyloids are structures that are formed in a process of self-assembly," explains Prof. Ehud Gazit. "It has long been known that amyloids are associated with severe diseases of the central nervous system, such as Alzheimer's, Parkinson's, ALS and Huntington's, and previous experiments in our laboratory have shown that they are also characteristic of genetic metabolic diseases. In these diseases, a gene responsible for the production of an enzyme that breaks down a certain metabolite (a substance that participates in the body's metabolism) is damaged, and in the absence of the enzyme, large amounts of that metabolite accumulate in the body, the accumulation of which leads to the formation of amyloid structures that can cause severe damage. Every newborn in Israel is tested for some of these diseases, because only early detection can prevent serious damage. As of today, a significant number of these diseases have no effective treatment, and the patients must avoid consuming foods that contain the substance that their bodies are unable to break down for the rest of their lives."

The baking preserve, a model for biological research, on a solid food substrate (left) and magnified using a light microscope (right). Credit: Photo courtesy of Gazit Lab
The baking preserve, a model for biological research, on a solid food substrate (left) and magnified using a light microscope (right). Credit: Photo courtesy of Gazit Lab

As a continuation of previous findings in Prof. Gazit's laboratory, in which the structures of amyloids were examined in test tubes in the laboratory, the researchers this time wanted to examine the accumulation of amyloids inside a living cell. To this end, they developed a model of yeast - single-celled organisms, which we usually use for baking and the production of alcoholic beverages, and which share a significant part of the genome with humans. Says Dr. Laor: "Yeast models of this type have many advantages in research, and they are even behind three Nobel Prizes in the last decade alone! We chose them because they allow us to carry out genetic manipulations in a quick, efficient and reliable manner, and in addition, they preserved essential metabolic pathways throughout evolution, which exist in all living things, and of course in humans as well."

The researchers created a mutation in the yeast system in the genes responsible for producing enzymes that break down an essential metabolite called adenine. In the absence of the decomposing enzymes, adenine molecules accumulated in the yeast cell, which clustered together into amyloid structures, causing the death of the cell. "We tested yeast with different levels of adenine," explains Dr. Laor. "We discovered that up to a certain level, the adenine does not kill the cell, and then suddenly, when it passes a certain level, the cell dies. The explanation for this is that a certain level of adenine is needed to trigger a self-assembly process, in which amyloid structures are formed. It turns out that these structures - and not the adenine per se - are what kill the cell." In the next step, the researchers added to the system tannic acid, a natural substance extracted from plants, which is known to inhibit the formation of amyloids. Indeed, the toxic structures were not formed, and the death of the yeast cells was prevented.

"Our research can be used as a platform for the development of drugs for hereditary and rare metabolic diseases that cause great suffering to patients, and most of them currently do not have an available and convenient solution," concludes Dr. Laor. "Each disease by itself is rare, but together they make up a significant part of all patients with congenital genetic diseases. Instead of an extreme diet for life, we seek to develop accessible medicines and treatments. Following the success of the first research in the yeast model, we submitted a patent for registration, and were able to raise funding from the university in order to continue developing the technology. Today, we continue to develop yeast models with mutations for additional metabolic diseases, and use them to try to discover potential drugs, which could improve the quality of life of the patients beyond recognition, and even save lives."

for the scientific article

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