Mice cured of progeria
Progeria, or Hutchinson-Guilford syndrome, is a rare genetic disease that manifests itself as premature aging of children and can significantly shorten their life expectancy. The study, which was the result of a collaboration between the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, the Broad Institute of Harvard University and the Massachusetts Institute of Technology and the Vanderbilt University Medical Center, showed the promise of gene editing by replacing nitrogenous bases for the treatment of progeria.
DNA consists of many combinations of four nitrogenous bases – adnin (A), cytosine (C), guanine (G) and thymine (T). Progeria is caused by a mutation in the nuclear lamin A (LMNA) gene, in one section of which the base of C is replaced by T. This change leads to an increase in the production of the toxic protein progerin, which dramatically accelerates the aging process.
Progeria is diagnosed during the first two years of life in about one in 4 million children, and almost all of these children in childhood and adolescence have health problems that are usually associated with old age, including cardiovascular diseases (heart attacks and strokes), hair loss, diseases of the musculoskeletal system, loss of subcutaneous fat and flabby skin.
To assess how changing this mutation might affect progeria symptoms in mice, the researchers used a new DNA base editing technique that allows one letter in the chain to be replaced with another without damaging the DNA.
In November 2020, the US Food and Drug Administration approved the first drug for the treatment of progeria – a drug called lonafarnib. However, drug therapy prolongs life, but does not cure progeria.
The DNA base editing method, which in the future may become a radical treatment option for progeria, was developed in 2016 by one of the authors of this study, David Liu from the Broad Institute, with partial financial support from NHGRI.
The CRISPR method, although revolutionary, cannot produce precise DNA changes in many cell types. Editing nitrogenous bases makes it extremely effective to replace one pair of bases with another, which, as the researchers suggested, will help cure progeria.
To evaluate the effectiveness of the base editing method, connective tissue cells taken from patients with progeria were used. Base replacement in the LMNA gene in vitro helped eliminate the mutation in 90% of cells.
After that, the researchers tested the gene editing technique in vivo. To do this, mice with a mutation that causes progeria were given a single intravenous injection of a mixture for DNA editing shortly after birth. This led to the successful restoration of the normal DNA sequence in the LMNA gene in a significant percentage of cells in various organs, including the heart and aorta.
Six months after treatment, many mouse cell types still retained the corrected DNA sequence. In the aorta, the results were even better than expected, as the edited cells seemed to replace the cells damaged by the mutation. The life expectancy of mice increased from seven months to almost one and a half years (the average normal life expectancy of mice used in the study was two years).
As the authors note, the ultimate goal of their work is to create a method of treating progeria in humans, but there are still important issues that need to be solved on model systems.
Article by L.W.Koblan et al. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on NIH materials: DNA-editing method shows promise to treat mouse model of progeria.