DNA-Editing Method Shows Promise for Treating Extreme Premature Aging

Hutchinson-Gilford Progeria Syndrome is a childhood disorder caused by mutations in one of the major architectural proteins of the cell nucleus. In HGPS patients the cell nucleus has dramatically aberrant morphology (bottom, right) rather than the uniform shape typically found in healthy individuals (top, right). (Photo courtesy Scaffidi P, Gordon L, Misteli T. PLoS Biology Vol. 3/11/2005, e395 via Wikipedia)

(CN) — A single tulip in a field of gardenias or an incorrect key on the wrong end of a keyboard can go unnoticed at first, but once pointed out the anomaly is hard to miss.

The same applies to genetic mutations. Progeria, the disease which causes children to age prematurely and rapidly, stems from a single misplaced gene. And in a study published Wednesday in the journal Nature, a breakthrough gene-editing method developed by researchers at the Broad Institute of MIT and Harvard, along with other collaborators, shows promising results in treating the mutation.

Hutchinson-Gilford progeria syndrome causes children to lose their hair and hearing, suffer from joint stiffness, loss of muscle, taut skin and even risk heart defects or stroke — all typically ailments of much older people. Children with the syndrome typically live until about age 13.

Researchers from the National Human Genome Research Institute (NHGRI) and other collaborators used the adenine base editing (ABE) technique on connective tissue cells taken from children with progeria. The technique, when applied to the LMNA gene, fixed over 90% of the cells affected by the progeria mutation.

“As a physician-scientist, it’s incredibly exciting to think that an idea you’ve been working on in the laboratory might actually have therapeutic benefit,” said Dr. Jonathan Brown, assistant professor of medicine at Vanderbilt University, in a statement accompanying the study. “Ultimately our goal will be to try to develop this for humans, but there are additional key questions that we need to first address in these model systems.”

Senior author Dr. David Liu at the Broad Institute developed the gene-editing process in 2016 through funding from the NHGRI. He said the base-editing process is effective in treating a disease like progeria, because editing techniques like CRISPR engineering cannot make precise DNA changes in certain cells.

The simplest explanation Liu offers for his technique is that it’s like a find-and-replace function in a word processor. The edited gene corrects the mutation by changing a T base into a C base.

Researchers also injected edited cells into a dozen mice with the progeria-causing mutation soon after they were born as part of his research and the gene editing process restored the DNA sequence, effectively correcting the cells in the heart, aorta and other organs of the mice according to the study authors.

Six months after being treated, most of the mice cells remained corrected and astoundingly, study authors say the edited cells began to replace the progeria-mutated cells, which eventually began to drop out from early deterioration.

The lifespan of the mice jumped from seven months to almost 1.5 years. Previous attempts to treat progeria have focused on reducing the amount of the toxic progerin that’s produced as a result of the mutation.

In November 2020, the U.S. Food and Drug Administration approved the medication Lonafarnib to treat progeria. It’s the first licensed therapy for the disease, but researchers argue it only partially alleviates the symptoms.

The ABE technique requires more research into how it can treat progeria and how a patient’s immune system will respond. While lingering questions about dosages remain and some side effects included liver tumors found in the longest-living mice, researchers say it’s a step in the right direction.

The moral implications of gene-editing were once the hypothetical thought exercise of old sci-fi novels. But in recent decades the concept of an engineered human being came into clearer focus, raising alarms about editing birth defects before a child is born. Other researchers say the time of “designer babies” remains a long way off.

But the method deployed by the base gene editing team at the Broad Institute is applied to living specimens — a correction to an unpredictable mutation.

“These findings suggest a potential therapeutic strategy for (Hutchinson-Gilford progeria syndrome) that directly corrects the causative mutation in vivo, and will inform applications of base editors in the treatment of other genetic diseases,” the study authors wrote.

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