'A cause for celebration': New gene editing tool offers promise of treating many genetic diseases

A woman's gloved arm reaches down into a plastic tub and carefully gets hold of a mouse. Caught on video, the woman speaks in a coaxing voice as the tiny animal quivers, but stays put. The mouse's coat is speckled with grey, and the lab technician says it's clear he isn't feeling well.

In a second tub, she points to several fast-moving mice. They all look healthy and active, with sleek, black coats. If she picked them up, she says, they would jump out of her hand.

All of these animals are genetically identical – almost.

If their genes were a book 2.7 billion letters long – just a little shorter than the King James Authorized Bible – only one letter would be different between them. 

Scientists have shown they can change that one letter and create healthier, longer-lived mice.

Their study, published Wednesday in the journal Nature, demonstrates a tool that can correct the kind of single-letter genetic mistakes that cause thousands of diseases.

"There’s a long road" before the tool, called a base editor, can be used to treat a genetic disease, says the paper's senior author, David Liu, a chemist at Harvard University. "But establishing that a base editor can correct a mutation that causes a systemic and devastating genetic disease in an animal, rescuing many of the symptoms of the disease and greatly extending lifespan is a good start!"

In this case, Liu and his colleagues repaired a gene that, when mutated, causes progeria, an ultra-rare disease leading to premature aging. The average lifespan of someone with progeria is just 14, and they die of conditions such as heart disease that usually kill people decades older.

Previous gene editing tools work like scissors to cut the double-stranded DNA that serves as life's blueprint. But treating most genetic diseases requires precise correction of the mutation rather than disrupting the gene, says Liu, vice chair of the faculty at the Broad Institute of Harvard and MIT, a biomedical and genomic research center. 

"For the vast majority of known genetic mutations that cause disease, it's difficult to understand how destroying the gene is going to benefit patients," he says.

Instead, a base editor tool works like a pencil, capable of erasing and rewriting a single letter mistake.

Correcting the genetic error in the mice is a huge scientific achievement, says Fyodor Urnov, a gene editing expert at the University of California-Berkeley, who was not involved in the new research.

Although there is a long way to go before a similar error is fixed in a person, Urnov likens the findings to climbing halfway up Yosemite's El Capitan without ropes.

"It's such a cause for celebration," Urnov says enthusiastically. "There's a lot of climbing that lies ahead and a lot of danger and a lot of unpredictability, but the part they just traversed, first, is a breathtaking achievement and second, is the riskiest."

The field of genetic engineering has moved forward in fits and starts for three decades, pocked with tragedies, such as the death of teenager Jesse Gelsinger in 1999, and crises such as the revelation in 2018 that Chinese scientist He Jiankui gene edited embryos leading to the birth of three babies. He is behind bars, and no other scientist has reported editing viable human embryos.

He used a gene editing tool called CRISPR-Cas9, developed earlier in the decade by two women, Jennifer Doudna of Berkeley and French scientist Emmanuelle Charpentier, who won the 2020 Nobel Prize in Chemistry for their achievement.

CRISPR has been shown in the past year to work effectively in people.

In March, a paper revealed it had been used in the eye to treat a genetic form of blindness. Last month, researchers showed a patient with sickle cell disease and another with the blood disorder beta thalassemia were able to stop regular transfusions in the year since their blood cells were gene edited, and the sickle cell patient has avoided pain crises.

CRISPR-Cas9 was used as a starting point for the new base editors developed in Liu's lab by then-graduate students Alexis Komor and Nicole M. Gaudelli, though not all base editors rely on CRISPR technology.  

The base editor used in the new study changes one DNA letter to another using a protein that took years of work to evolve. Then it nicks the opposite strand – the unedited one – so the cell’s repair mechanism fixes the DNA letter on that strand, too. 

DNA is shaped like a "double helix," a twisted ladder made up of pairs of nucleotides, abbreviated as letters. A always pairs with T, and C pairs with G. The tool is called an A base editor, or ABE, because it changes an A-T pair to a G-C pair.

Nearly half of the thousands of diseases caused by single-letter mistakes could be corrected by making this type of change.  

Progeria is one of those diseases.

Leslie Gordon, a pediatric researcher at the Alpert Medical School of Brown University, and a co-author on the new paper, has been trying to effectively treat progeria since her son Sam Berns was diagnosed with the condition at age 2 in 1998. He died in 2014.

There are 19 people in the USA and about 400 worldwide with progeria, which is also called Hutchinson-Gilford progeria syndrome.

In November, the Food and Drug Administration approved the first treatment for the disease, Zokinvy (lonafarnib), from a class of drugs usually used to treat cancer. A 13-year study showed the drug can provide an extra 2.5 years of life for a child with progeria – an improvement but far from a cure.

"It's sort of a beacon that says we really can help these kids," says Gordon, who co-founded the Progeria Research Foundation and serves as its volunteer Medical Director.

Gene editing offers the prospect of even more improvement, because it addresses the underlying cause of the disease, she says.

The progeria mice used in the study were specially developed to have the same gene that's mutated in humans. That work was led by Dr. Francis Collins, the head of the National Institutes of Health and a co-author on the paper.

The fast-moving mice treated with the base editor were in that second plastic tub. They were healthier, much more active and lived a median of 510 days, compared with 215 days for the mice with progeria. That's the cusp of old age, Liu says.

"The results were much better than we expected," Liu says.

The mice that received the one-time treatment with the gene editor when they were 14 days old fared better than those treated at 3 days old. The gene editor was delivered by a virus modified to be harmless, though it can cause liver problems in mice.

Liu, whose lab developed a C-to-T base editor that can correct 14% of all single-letter gene mutations, is working to address the remaining types of tiny genetic errors.

Several more years of research will be needed before the technique can be tested in children with the disease, including safety studies and testing in monkeys.

"There's more to be done," Gordon says. "This is the initial big, beautiful hit on those disease features in the animal model. That's very important."

Contact Karen Weintraub at kweintraub@usatoday.com

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