DNA-editing method promises to process mouse model of progeria

Press release

Wednesday, January 6, 2021

Using a newly developed basic DNA editing technique, researchers are correcting the disorder of accelerated aging.

Researchers have successfully used a DNA-editing technique to extend the lifespan of mice with the genetic variation associated with progeria, a rare genetic disorder that causes extreme premature aging in children and can dramatically reduce their life expectancy. of life. The study was published in the journal Nature, and was a collaboration between the National Human Genome Research Institute (NHGRI), which is part of the National Institutes of Health; Broad Institute at Harvard and MIT, Boston; and Vanderbilt University Medical Center, Nashville, Tennessee.

DNA is made up of four chemical bases – A, C, G, and T. Progeria, also known as Hutchinson-Gilford progeria syndrome, is caused by a mutation in nuclear lamin A.(LMNA) gene in which a base of DNA C is changed to T. This change increases the production of the toxic protein progerin, which causes the rapid aging process.

About 1 million in 4 children are diagnosed with progeria in the first two years after birth, and virtually all of these children develop health problems during childhood and adolescence that are normally associated with old age, including cardiovascular disease (heart attack and stroke), hair weight loss, skeletal problems, loss of subcutaneous fat and hardened skin.

For this study, the researchers used a revolutionary DNA editing technique called basic edition, which substitutes a single letter of DNA for another without damaging the DNA, to study how changing this mutation might affect progeria-like symptoms in mice.

“The toll of this devastating disease on affected children and their families cannot be overstated,” said Francis S. Collins, MD, Ph.D., senior researcher in the medical genomics and metabolic genetics branch of NHGRI, NIH director and corresponding author on the paper. “The fact that a single specific mutation causes disease in almost all affected children made us realize that we may have tools to correct the root cause. These tools could only be developed through long-term investments in basic genomics research. “

The study follows another recent step in progeria research, as the The United States Food and Drug Administration approved the first progeria treatment in November 2020, a medicine called lonafarnib. Drug treatment offers some prolongation of life, but it is not a cure. The DNA editing method may provide an additional and even more dramatic treatment option in the future.

David Liu, Ph.D., and his laboratory at the Broad Institute developed the Basic Editing Method in 2016, funded in part by NHGRI.

“CRISPR editing, while revolutionary, cannot yet make precise changes to DNA in many types of cells,” said Dr. Liu, lead author of the article. “The basic editing technique we have developed is like a find-and-replace function in a word processor. It is extremely effective at converting base pair to base pair, which we believe would be powerful in treating a disease like progeria. ”

To test the effectiveness of their basic editing method, the team initially collaborated with the Progeria Research Foundation to obtain connective tissue cells from patients with progeria. The team used the base editor on theLMNAgene in patients’ cells in the laboratory. The treatment fixed the mutation in 90% of the cells.

“The Progeria Research Foundation was delighted to collaborate on this foundational study with Dr. Collins’ group at NIH and Dr. Liu’s group at the Broad Institute,” said Leslie Gordon, MD, Ph.D., co-author and director from The Progeria Research Foundation, which partially funded the study. “These study results present an exciting new avenue for the investigation of new treatments and cure for children with progeria.”

Following this success, the researchers tested the gene-editing technique by administering a single intravenous injection of the DNA-editing mixture to nearly a dozen mice carrying the progeria-causing mutation soon after birth. The gene editor succeeded in restoring the normal DNA sequence of theLMNAgene in a large percentage of cells in various organs, including the heart and aorta.

Many types of mouse cells still maintained the corrected DNA sequence six months after treatment. In the aorta, the results were even better than expected, as the altered cells appeared to have replaced those that carried the progeria mutation and gave up the early deterioration. Even more dramatically, the lifespan of treated mice increased from seven months to almost a year and a half. The average normal lifespan of the mice used in the study is two years.

“As a physician-scientist, it’s incredibly exciting to think that an idea you worked on in the lab might actually have a therapeutic benefit,” said Jonathan D. Brown, MD, assistant professor of medicine at the Vanderbilt University Medical Center Division of Cardiovascular Medicine. “Ultimately our goal will be to try and develop this for humans, but there are other key questions we need to address in these model systems first.”

Funding for the study was supported in part by NHGRI, NIH Common Fund, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Engineering, National Institute of General Medical Sciences, National Heart, Lung and Blood Institute and the National Center for the Advancement of Translational Sciences.

The National Human Genome Research Institute (NHGRI) is one of 27 institutes and centers of NIH, an agency of the Department of Health and Human Services. NHGRI’s intramural research division develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information on NHGRI can be found at: https://www.genome.gov.

About the National Institutes of Health (NIH):The NIH, the national agency for medical research, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

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