Changing our DNA: “The era of human therapeutic gene editing has arrived”

While Rose spent her short life helping break the stigma attached to a devastating disease, geneticist David Liu dedicated his career to developing ways to alter the genetic code that claimed his life at such a young age.

“That a single misspelling in her DNA ended Adalia’s life so soon is a loss to all of us,” said Liu, professor of chemistry and chemical biology and director of the Merkin Institute of Transformative Technologies. in Healthcare at Harvard University.

“I didn’t have the chance to meet Adelia before she passed away in January. But every progeria patient I’ve met has been warm, charming, articulate and deeply inspiring,” Liu told CNN.

In his Harvard lab, Liu and his team have invented new ways to repair mutated genes that damage DNA less than previous technologies. One of his lab’s innovations is called a base editor, which he used last year to cure progeria in mice. There are four bases in DNA: adenine (A), cytosine (C), guanine (G) and thymine (T). These form specific pairs: A with T and G with C.

Liu hopes the tool will soon be used in human clinical trials to reverse progeria in humans.

“The base editor goes into the cells of the animal, finds the error that in progeria is a C to a T, and changes the T back to C,” Liu told an audience Tuesday at the conference. Life Itself, a conference on health and health. wellness event presented in partnership with CNN.

“And that’s it. We never go back to the patient – it’s a one-time treatment that permanently corrects the mutation that causes the disease,” said Liu, who is also vice president of faculty at the Broad Institute. from MIT and Harvard. , a biomedical and genomics research center in Cambridge, Massachusetts.

Six months after announcing the success of progeria, Liu and scientists at St. Jude Children’s Research Hospital announced that they had used base editors to reverse sickle cell disease in mice.

“The era of human therapeutic gene editing is not just coming. It’s already here,” Liu told the Life Itself audience.

The advantage of a “nick”

Scientists modify genes using enzymes that have been designed to target a specific DNA sequence, cut out the offending genetic material and insert replacement DNA. For decades, however, known methods of modifying our genetic code have been clumsy, often missing their mark or cutting off too much or too little genetic material.

What is CRISPR and why is it controversial?
The arrival of CRISPR systems in the 1990s and more particularly CRISPR-Cas-9 in 2013 heralded a new, more elegant way of editing genes. CRISPR uses what is called guide RNA to bring the Cas-9 enzyme to a more precise location on the DNA strand to make the cut.
After years of verification, the United States Food and Drug Administration approved CRISPR-Cas-9 in 2021 for use in human clinical trials for sickle cell disease. Clinical trials are also underway to test the safety of gene editing in a blood disorder called beta-thalassemia, leber congenital amaurosis, which is a form of hereditary childhood blindness, blood cancers, leukemia and lymphoma, diabetes of type 1 and HIV/AIDS, to name a few.
In 2021, researchers reported that they had successfully edited a rare and painful condition called transthyretin amyloidosis in six people with just one treatment. This fatal disease causes a protein called TTR to fold into clumps and attack the heart and nerves. The study, published in August, reported that TTR levels in some people fell by an average of 87% after treatment.
A researcher performs a CRISPR-Cas-9 process at the Max-Delbrueck-Center for Molecular Medicine in Berlin.

However, like older editing technologies, CRISPR-Cas-9 cuts both DNA strands, which has some drawbacks, Liu said. For one thing, some cells rolled back edits after they were made, he said, “so the overall editing efficiency was very low.”

Liu’s team found that if you cut just one strand of the DNA double helix with CRISPR-based technology and “cut” the other, the cell was more likely to implement the corresponding change. on the second strand without complaining – and with fewer mistakes.

Editing larger DNA sequences

Liu and his team also invented another type of CRISPR-based tool called a master editor, which could make larger and more complex edits to DNA than basic editors could not.

Unethical experiments' painful contributions to medicine today
In tests using lab-grown human cells, Liu’s team used master editing to correct the genes responsible for Tay-Sachs disease, a fatal neurological disorder that attacks in the first few months of life. Children with Tay-Sachs usually die a few years after symptoms start.

“An analogy I like to use is that the original CRISPR-Cas_9 is like scissors that cut DNA. Core editors are like pencils that precisely correct letters by changing them to one of four different letters” , explained Liu. “And master editors are like molecular word processors that do true search and replace of larger sequences.”

Only a third of the 75,000 known “spelling mistakes” that cause genetic diseases can be corrected by grassroots editors, Liu said. “But add our main editor, and in between, they can finally free us from the vast majority of misspellings in our DNA,” he told the Life Itself audience.

“We have to make sure that all of these different technologies go through clinical trials very carefully,” Liu added. “But if they prove to be safe and effective, then one could imagine treating not just the rare misspellings that cause serious genetic diseases, but perhaps even treating genetic variants that we know contribute to many terrible diseases like Alzheimer’s disease or hypercholesterolemia.”

In a 2019 blog post, former National Institutes of Health director Dr. Francis Collins called Master Editing “groundbreaking”, saying that Liu and his team had “used their new system to insert new DNA segments up to 44 letters long and to remove segments at least 80 letters long.”

However, Collins added, “It’s unclear whether master editing can insert or delete DNA the size of complete genes – which can contain up to 2.4 million letters.”

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Gene editing will not be a solution for all of life’s diseases, Liu warned. For example, infections and cancer cells are two areas that are not well suited for gene editing, as you would have to touch every cell to stop the disease.

“But with many genetic diseases, we often only need to modify 20% or 30% of the tissues to save the genetic disease,” Liu said. “That’s what we’ve seen with progeria and sickle cell disease in mice. A little editing can go a long way to saving these diseases in animals, and we’re thinking about humans too.”


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