RARE Daily

Study Suggests Genetic Editing Could Correct Rare Disease that Causes Rapid Aging

January 13, 2021

It was only at the end of 2020 that the U.S. Food and Drug Administration approved Zokinvy, the first drug to treat Hutchinson-Gilford Progeria Syndrome, an ultra-rare genetic disease that causes people to age rapidly. Less than two months later, the prospect of using gene editing to correct the underlying mutation in progeria, has come to life.

On the heels of the Zokinvy approval, researchers published a study in the journal Nature that suggests in vivo gene editing could correct the root cause of the disease. The study in mice by researchers at The Broad Institute, the National Institutes of Health, the Progeria Research Foundation, and elsewhere provide hope for that a newer form of gene editing could arrest the disease.

“Progeria is now on the forefront of a genetic therapy that could make a huge difference for these children,” said Leslie Gordon, medical director of the Progeria Research Foundation and study co-author.  

Progeria is fatal pediatric disease that affects about 400 children worldwide. Children with Progeria die of heart disease at an average age of 14.5 years, due to premature atherosclerosis resulting in heart attacks. The recently approved therapy Zokinvy increases average lifespan by 2.5 years and improves some symptoms of Progeria, but it does not address the genetic mutation that causes the disease. 

The condition is caused by a point mutation—a single letter change in the LMNA gene, which encodes the lamin A protein. The result of the change is the production of an aberrant protein known as progerin. Lamin A protein is part of the structural scaffolding that holds the nucleus together. Researchers believe that progerin may make the nucleus unstable, and that cellular instability may lead to the process of premature aging in Progeria. 

Researchers found by using a form of gene editing known as base editing, they could reverse the mutation that causes progeria. By editing the genes of mouse models, they were able to improve disease symptoms and increase lifespans.

The effects were dramatic. With a single injection of a base editor designed to correct the disease-causing mutation, mice survived 2.5 times longer than control untreated progeria mice. That improvement gave them a lifespan that corresponded with the start of old age in healthy mice. All of the treated mice also retained healthy vascular tissue. In children with progeria, the loss of vascular integrity is a predictor of mortality.

“To our knowledge, this work resulted in the strongest rescue of the symptoms of progeria by multiple measures,” said The Broad Institute’s David Liu, who is co-lead and co-corresponding author on the Nature study. “Five years ago, we were still finishing the development of the very first base editor. If you had told me then that within five years, a single dose of a base editor could address Progeria in an animal at the DNA, RNA, protein, vascular pathology, and lifespan levels, I would have said ‘There’s no way.’”

NIH Director Francis Collins, a co-author on the study, has had a long connection with progeria. In 2003, his lab at NIH discovered the mutation that causes disease. The discovery, he said, raised the possibility that correcting that genetic misspelling could treat or cure a child with the disease, but the tools to edit DNA therapeutically didn’t exist.

“To be honest, I didn’t think that would be possible in my lifetime,” he wrote on his blog.

Now, though, with advances in genetic research, the promise of using gene editing is creating new approaches to treat a range of genetic diseases. While much attention has been paid to CRISPR, the discovery of which garnered a Nobel Prize in 2020 for Emmanuelle Charpentier and Jennifer Doudna, it has its limits. Collins notes that while CRISPR is a powerful editing tool, it works best as a way to knock out genes rather than correct them. Alternative systems, though, are providing new promise.

The Broad Institute’s Liu, developed one such alternative to CRISPR, which is base editing. CRISPR has been described as a pair of genetic scissors. It’s good at cutting. Collins explains that base editors don’t cut. Instead, they convert one DNA letter to another by enzymatically changing a DNA base to become a different base. He compares it to the find-and-replace function on a word processor.

“We are hopeful this gene editing work might eventually lead to a cure for progeria. But mice certainly aren’t humans, and there are still important steps that need to be completed before such a gene-editing treatment could be tried safely in people,” said Collins, “In the meantime, base editors and other gene editing approaches keep getting better—with potential application to thousands of genetic diseases where we know the exact gene misspelling. As we look ahead to 2021, the dream envisioned all those years ago about xing the tiny DNA typo responsible for progeria is now within our grasp and getting closer to landing in the “can do” category.”

Thanks to Pfizer, Inc., Bluebird, and Novartis Gene Therapies for their support of this article, part of our Platforms of Hope: Advances in Gene Therapy and Gene Editing series.

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