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IN THE USA approved the first drug for patients with Hutchinson-Guildford Progeria – an incurable congenital disease reminiscent of premature aging. It is a repurposed anticancer drug. According to the results of clinical trials, it can prolong the life of patients from several months to several years – depending on what age and how long it is taken.
Progeria Hutchinson-Guildford is the most famous and most severe of the diseases of premature aging. It manifests itself from birth, when children are born with a number of signs typical for the elderly: they have wrinkled skin, swollen joints, a disproportionately wide head and a “beak-shaped” face narrowed to the chin.
The cause of all these pathologies – as well as many others related to internal organs – is the protein lamin A. Normally, it is needed to organize the space inside the cell nucleus: it lines the nuclear membrane from the inside and fixes DNA strands around it. To ensure that lamin A is near the nuclear envelope, it is recognized by the enzyme farnesyltransferase and hangs a hydrophobic “tail” on it. With this “tail,” lamin A is anchored in the membrane, taking its place in the nucleus. Later, other enzymes cut off this “tail”, and lamin A remains close to the shell, but is not directly associated with it.
People with progeria have a mutation in the lamin A gene that makes the protein shorter than usual. Therefore, at first everything goes according to plan: farnesyltransferase recognizes it and hangs a “tail” on it, and the “tail” of the mutant protein is incorporated into the nuclear membrane. But after that, other enzymes cannot rid it of the “tail”, since the mutant lamin A is deprived of a site for them to grab onto. Therefore, it remains embedded in the membrane of the nucleus, due to which the entire nucleus loses its elasticity, the organization of DNA inside is disrupted, it becomes difficult for the cell to divide and copy genetic information without errors. As a result, people with this mutation rarely survive the 15th birthday and die from typical age-related diseases, such as heart failure or stroke.
–Here’s What Happens in the Nuclear Wall of Mutant Lamin A Cells
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Since this mutation always occurs again and this happens quite rarely, it is usually not possible to identify the disease in the early stages. It is also still impossible to repair the lamin A gene in all the cells of a patient with Progeria. Therefore, the only way to prolong their life is to try to compensate for the lamin A defect. This is how lonafarnib, the first approved progeria drug, works. It is a well-known anticancer drug.
Lonafarnib serves as a farnesyltransferase blocker. It prevents her from hanging a hydrophobic tail on lamin A, so the mutant protein, although it does not start working at full strength, still does not deform the membrane of the cell nucleus. This is enough to reduce mortality in patients with progeria. By data the company that manufactures lonafarnib, within two years of taking the drug, the risk of death in patients is reduced by 77 percent. Among those who took lonafarnib for more than 11 years in long-term trials, life expectancy increased by 2.5 years compared to the placebo group.
–Patients with progeria are more likely to survive for 2.5 years with lonafarnib (blue line). On the right is a photo of cell nuclei in a healthy cell, a cell with progeria and a cell under the influence of lonafarnib, respectively.
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Thus, a drug has finally appeared in the world that at least partially solves the problem of premature aging. However, it has nothing to do with anti-aging drugs, “usual”. Although the processes that lead progeria sufferers to early death are very similar to natural aging mechanisms, their cause is quite different. Therefore, lonafarnib will not help people without an appropriate mutation and with a normal structure of the cell nucleus to cope with aging.
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