Progeria: gene therapy gives hope

Progeria, or Hutchinson-Guilford syndrome, is a rare hereditary disease characterized by rapid aging of the body, beginning in early childhood. In 2003, Nicolas Levy established that the cause of the development of this disease is a mutation of the LMNA gene encoding the nuclear protein lamin A. In carriers of this mutation, an abnormal version of the protein, called progerin, accumulates in the nuclei of cells and has a toxic effect, manifested by various deformations and disorders of the cells. Subsequently, it was demonstrated that progerin accumulates in the cells of healthy people, which clarified the relationship between the disease and physiological aging.

In recent years, researchers have made significant progress in the study of progeria and in 2008, 12 children with this disease had the opportunity to participate in a clinical trial in which they were injected with a combination of two drugs that was supposed to slow down the process of premature aging. One of the drugs included in the combination refers to statins used to lower cholesterol levels in the blood, and the second – to aminobisphosphonates used in the treatment of osteoporosis and for the prevention of complications in certain types of cancer. The purpose of using both drugs is the chemical modification of progerin, which reduces its toxicity, but does not affect the process of its accumulation in the nuclei of cells. Until now, researchers have not been able to study this aspect of the disease due to the lack of an adequate animal model.

To create such a model, a group of Spanish and French scientists working under the leadership of Carlos López-Otín from the University of Oviedo introduced the LMNA gene carrying the G609G mutation, equivalent to the human G608G mutation, into the genome of mice, which allowed them to reproduce the exact pathogenetic mechanisms of progeria. 3 weeks after birth, such animals begin to develop physical and metabolic symptoms of aging, which reduces their life expectancy to an average of 103 days – about 7 times compared to normal.

Using the new model, the researchers developed and tested a method of gene therapy aimed at suppressing progerin production. The method is based on a technology that the authors called “vivo-morpholino”, which consists in the introduction of synthetic antisense oligonucleotides to animals that block the synthesis of lamin A and, accordingly, progerin. This approach made it possible to increase the life expectancy of genetically modified animals to an average of 155 days; the maximum indicator at the same time was 190 days.

The researchers plan to conduct a clinical study of the gene therapy method they have developed, possibly in combination with pharmacological drugs. Currently, they are searching for more effective methods of delivering antisense oligonucleotides to cell nuclei.

Article by Fernando G. Osorio et al. Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging is published in the journal Science Translational Medicine.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on INSERM (Institut national de la santé et de la recherche médicale):
Progeria: promising results from new gene therapy on animals.

01.11.2011