Aging already in the early years of life: the genetic disease progeria is a bad fate for those affected. But now a new therapy option could develop, according to a study: Researchers were able to correct the gene mutation responsible for the disease in mice by exchanging the affected DNA base. This reduced the symptoms in the “progeria mice” and their life expectancy increased significantly. Further studies must now show whether the method is also suitable for use in human progeria patients.
The so-called Hutchinson-Gilford progeria syndrome is rare, but particularly cruel: While other children grow and mature, those affected suffer from stunted growth and turn into young old people. Doctors often diagnose symptoms in around one in four million children in their first or second year of life. Children’s skin begins to age, hair falls out and joint problems and cardiovascular diseases increasingly develop. Those affected have therefore often only reached an age of around 14 years. Last year there was good news for progeria patients: The drug Lonafarnib was approved, which enables a certain life extension. However, the active ingredient only intervenes in a certain process in the context of the development of the disease and is therefore only effective to a limited extent. The new approach, however, tackles the problem at the genetic root.
A small mutation with fatal consequences
The cause of the disease is a mutation in the so-called lamin-A gene, which carries the information for an important component of the nuclear membrane in the cells of the body. This hereditary disposition shows a small but serious flaw in progeria patients: In their lamin A gene, a DNA base has been changed from cytosine (C) to thymine (T). This mutation leads to the production of the protein progerin, which causes the rapid aging process. A team of US researchers has now applied the lever to this point mutation. “The fact that a single specific mutation causes the disease enables the use of DNA-editing techniques to correct it,” says co-author Francis Collins of the National Human Genome Research Institute in Bethesda.
There have already been attempts to use the well-known Crispr / Cas9 gene editing method to specifically repair the mutation in the gene. But this procedure carries the risk of collateral damage: problematic DNA fragments or cuts outside the actual target area can arise. The researchers therefore now use the newer DNA base editing technique. A modified form of the Crispr / Cas9 system is used here, through which individual bases can be changed at a specific genomic location. The important difference is that the base editors do not split the phosphate framework of the DNA, so that no double-stranded DNA breaks can occur.
Promising success
The researchers first tested the base editing method for correcting the genetic defect on connective tissue cells grown in the laboratory from progeria patients. This led to a promising result: the treatment was able to correct the mutation in around 90 percent of the cells. So the researchers then went on to animal experiments: They used mouse breeding lines that represent a model of progeria. The animals also have the corresponding mutation in the lamin A gene, show signs of premature aging and have a significantly shortened life expectancy. The scientists administered these “progeria mice” an intravenous injection of the DNA editing substance shortly after birth. Then they examined the effect and the development of the test animals.
It was found that the Gene Editor was able to successfully produce the normal DNA sequence of the Lamin A gene in a significant percentage of cells in various organs of the mice. The researchers emphasize that the effect on cells in the heart and aorta is of great importance. Many of the cell types in the mice retained the corrected DNA sequence even six months after treatment, and the production of progerin decreased sharply, the analyzes showed. This significantly alleviated the symptoms of the test animals and, above all, the effect of the treatment was reflected in the lifespan: it increased from seven months to an average of 1.5 years and thus approached the normal life expectancy of mice, which is around two years.
“It was exciting to see the signs that the approach could indeed have therapeutic benefits,” said Jonathan Brown co-author at Vanderbilt University Medical Center in Nashville. “Now it is our goal to make the procedure a treatment option for humans. First of all, there are still important questions that we still have to clarify in the mouse model system, ”emphasizes the researcher. Wilbert Vermeij and Jan Hoeijmakers from the Oncode Institute in Utrecht also see reason for hope for progeria patients: “If the safety of base-editing treatments can be guaranteed in humans, then it is a very promising approach to treating people who are under suffer the consequences of this genetic mutation, ”the scientists write in a comment on the study.
Source: National Human Genome Research Institute, Technical article: Nature, doi: 10.1038 / s41586-020-03086-7