When popular YouTube star Adalia Rose died earlier this year, she looked like a sick woman in her 80s. In reality, she was just 15 years old, a victim of progeria, an extremely rare genetic disorder caused by a single mutation in one of the 3 billion base pairs that make up human DNA. Completely normal in mind and spirit, children with progeria age at a very rapid rate, often dying in their teens.
Rose won the hearts of her 3+ million YouTube subscribers and 12 million Facebook followers with a joyful, positive outlook and zest for life. With the help of her mother, she has shared details of the painful and debilitating illness through lovely animated videos, leaving plenty of room for her dance moves and various makeup tutorials.
“I look sexy!” she told the audience, tossing her blue-tipped blonde hair over her shoulder with a Lizzo touch, before sitting down to explain to onlookers the types of meds she took and why she lost sight in one eye.
While Adalia spent her short life helping to break the stigma associated with a devastating disease, geneticist David Liu has dedicated his career to developing ways to alter the genetic code that took her life at such a young age.
“That a single mistake in her DNA ended Adalia’s life so soon is a loss for us all,” Liu, a professor of chemistry and chemical biology and director of the Merkin Institute for Transformative Health Technologies at Harvard University, told the BBC. United States.
“I didn’t get a chance to meet Adalia 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 lab at Harvard, Liu and his team invented new ways to repair mutated genes that are less damaging to DNA than previous technologies. One of his lab’s key innovations is a base editor, a tool that can correct errors in the four most common bases of DNA, Liu told an audience at Life Itself, a health and wellness event presented in partnership with CNN .
“These mistakes in our DNA have collectively caused thousands of disorders that affect hundreds of millions of people and their families,” Liu said.
These four DNA bases – adenine (A), cytosine (C), guanine (G), and thymine (T) – form specific pairs that must always be matched with each other: A with T and G with C.
Last year, Liu and his team used a base editor to deal with misplaced progeria genes in mice. He says he hopes clinical trials for children with progeria can begin in the near future.
“The base editor goes into the animal’s cells, looks for the error, which in progeria is a C to a T, and changes the T back to a C,” said Liu, who is also vice president of the faculty at the Broad Institute. of MIT and Harvard, a center for biomedical and genomics research in Cambridge, Massachusetts.
Liu’s team further found that base editors worked especially well if you “cut” the unedited strand of the DNA double helix, persuading the cell to copy the desired edit onto the second strand.
“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,” Liu said.
Six months after announcing success with progeria, Liu and scientists at St. Jude Children’s Research Hospital announced that they 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.
Next generation of gene editors
Scientists edit genes using enzymes that are designed to target a specific sequence in the DNA, cut out the offending genetic material, and insert replacement DNA. For decades, however, known methods of modifying our genetic code were clumsy, often missing the mark or cutting too much or too little genetic material.
The arrival of CRISPR systems in the 1990s and specifically CRISPR-Cas-9 in 2013 heralded a new and more elegant way to edit genes. CRISPR uses what’s called guide RNA to bring the Cas-9 enzyme to a more precise point on the DNA strand to make the cut.
CRISPR-Cas9 evolved in bacteria to disrupt the genes of infecting viruses by cutting both strands of DNA, essentially turning off the gene, Liu explained to the audience.
After years of verification, the Food and Drug Administration (FDA), an agency similar to Anvisa in the United States, 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’s congenital amaurosis, which is a form of inherited childhood blindness, blood cancer, leukemia and lymphoma, type 1 diabetes, and HIV. , 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 a single treatment. The 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 declined by an average of 87% after treatment.
Editing longer DNA sequences
Cutting a double helix to silence a gene, however, did not solve the problem of the many genetic diseases that need a computer-like “find and replace” solution, Lui told the audience.
The discovery of base editors that could convert one letter to another solved only part of this problem. An editor was needed that could perform larger and more complex edits to the DNA that base editors could not.
Step into the next generation: main edition.
“One analogy I like to use is that the original CRISPR-Cas-9 is like scissors that cut DNA. “And core editors are like molecular word processors that do true search and replace of larger sequences.”
Only a third of the 75,000 known “spelling errors” that cause genetic diseases can be corrected by base editors, Liu said. “But add our main editor, and between the two, they can finally free us from the vast majority of ‘spelling mistakes’ in our DNA,” he said.
In tests with human cells grown in the lab, Liu’s team used primary editing to correct the genes responsible for Tay-Sachs disease, a fatal neurological disorder that strikes in the first few months of life. Children with Tay-Sachs usually die within a few years of the onset of symptoms.
“We have to make sure that all these different technologies go through clinical trials very carefully,” added Liu. “But if they prove to be safe and effective, then one can imagine treating not just rare bugs that cause serious genetic disease, but perhaps even treating genetic variants that we know contribute to terrible diseases like Alzheimer’s disease or high cholesterol.”
In a blog post in 2019, former National Institutes of Health (NIH) director Francis Collins called the main edition “revolutionary”, saying that Liu and his team “used their new system to insert new segments of DNA of up to 44 letters and remove segments of at least 80 letters.” However, Collins added: “It is unclear whether primary editing can insert or remove DNA the size of complete genes – which can contain up to 2.4 million letters.”
Gene editing will not be a solution to all of life’s ailments, Liu warned. For example, infections and cancer cells are two areas that don’t mix well for gene editing, because you would have to touch every cell to stop the disease.
“But with many genetic diseases, we often only need to edit 20% or 30% of the tissue to get the genetic disease out,” Liu said. “That’s what we saw with progeria and sickle cell disease in mice. A little bit of editing can go a long way towards taking these diseases out of animals, and we think about people too.”
Source: CNN Brasil
