Gene Editing Technique Halts Premature Aging In Mice, Could It Help Children With Rare Disease?

A specialized gene editing technique that allows very small and precise changes to be made to the genetic code can halt a disease that causes premature aging in a mouse model and double the lifespan of the treated animals.

The hope is that this finding can be replicated in people with the same condition — a genetic disease called progeria — which currently has no cure. Children who develop the disease normally die around the age of 15 years.

Over the last decade, a new technique for editing genes called Crispr-Cas9, often just abbreviated to Crispr, has revolutionized molecular biology. A number of different people are behind the discovery and roll-out of Crispr technology, but two women in particular – Jennifer Doudna and Emmanuelle Charpentier were recognized for their work in this area and awarded the honor of the 2020 Nobel prize in Chemistry.

Now used in many labs around the world Crispr technology allows scientists to make small and precise changes to the DNA. This could be in plants, for example to make a food more nutritious or more resistant to pests. Or it can also be used to fight genetic diseases.

Since the discovery of Crispr, gene editing has become even more refined with the discovery of base editing. It was pioneered around 5 years ago in the lab of David Liu, a faculty member of the Broad Institute and a professor at Harvard University, who is behind the progeria research. This technique is even more precise than Crispr and allows one letter of the DNA code to be replaced with another.

A year after this new technique was discovered, Liu set up a biotech called Beam Therapeutics with two colleagues. Feng Zhang, a professor at MIT and faculty member at the Broad Institute – one of the pioneers of Crispr technology – and Keith Joung, a professor at Massachusetts General Hospital and Harvard Medical School.

Since then, the team at (and behind) Beam Therapeutics has been working hard to develop the first base edited therapies for genetic diseases. The company’s most advanced therapy is designed to treat the painful blood condition sickle cell disease, but is yet to pass through human trials.

Hutchinson–Gilford progeria syndrome or simply ‘progeria’ is caused by a single letter change in the genetic code of a gene called Lamin A in more than 90% of individuals who develop it. This single letter or 'base' change in the genetic code has devastating effects, resulting in early aging and cell death around the body and most children who develop the syndrome die in their mid-teens.

“This mutation, discovered in 2003 by Francis Collins's lab, results in a poisonous protein that has the potential to damage nearly all cells in the body by damaging the structure of a protein that helps hold the nucleus together,” David Liu, who led the research, told me.

Because the disease is caused by a single letter change in the DNA. It makes a good candidate for base editing therapy, but also makes it difficult to treat using other types of gene therapy including more standard gene editing technology such as Crispr. These methods are simply not precise enough.

To test whether their technology could successfully treat progeria, Liu and his team used base editing to correct the disease-causing mutation in a mouse model. The model was developed by Francis Collins’s lab at NIH and has two copies of the human gene variant that causes progeria. 

“First, we sought to test the possibility that directly correcting the mutation that causes progeria in an animal after birth might rescue the animal from some of the major symptoms of this devastating disease,” explained Liu. 

“But in a broader sense, we also sought to test the ability of base editors to correct a systemic genetic disease… long-term—that is, a genetic disease that affects more than one organ, which is thought to be especially challenging to treat.”

In this study, the researchers injected some of the mice born with progeria with their base editing treatment at around 14 days of age, which Liu says corresponds to about 5 years in humans. The rest were left as controls.

The scientists then watched the mice over time to see if the therapy had a noticeable effect. “As these mice passed 200 days of age, then 300 days, then 400 days, then 500 days, we realized the extent of the disease rescue was well beyond what had been achieved before, and we started freaking out, to use the scientific term,” says Liu.  

Untreated mice with progeria normally live around 7 months (approximately 210 days) before dying from symptoms of the disease. An average mouse aged 18 to 24 months (540—720 days) is considered ‘old’ roughly the equivalent of a human aged 56-69 years. Mice do sometimes live beyond 24 months, but this is unusual.

Most of the mice that received a single base editor treatment doubled their lifespan and reached early old age. In addition to this, these mice lacked characteristic signs of vascular cell damage commonly seen in animals and people with the condition.

“Five years ago, we were still working on the first base editor,” says Liu. “If you had asked me then how long it would be before a base editor might be used to treat progeria in a mouse, greatly extending its lifespan and rescuing the disease at the DNA, RNA, protein, and vascular pathology levels, I probably would have guessed at least a decade, optimistically!”

Liu and his colleagues and the team at Beam Therapeutics now hope to be able to begin clinical trials of this treatment in children with progeria, who currently have limited treatment options.

“Since we’ve developed many improved base editors since this study began, optimizing the base editors used, the delivery vectors used, the dosages needed, as well as the timing of the treatment to achieve a therapeutic benefit, all could help maximize the safety and efficacy of a potential future progeria treatment based on this work,” says Liu.

“Given the severity of the disease and the limited treatment options available to children with progeria, we are pursuing both approaches simultaneously.”