Advances in gene therapy have come a long way since the 1960s and 1970s, when scientists first conceptualized the idea of modifying genes in patients who suffered from debilitating congenital conditions such as sickle cell anemia and hemophilia.
Now there are gene therapies for the two conditions and even for certain cancers — but technical challenges remain, such as making sure the modified genes inside the patients are making enough of the protein their bodies lack.
That's why it's intriguing that scientists from the Baylor College of Medicine have published research in the science journal Nature Biotechnology that they say may crack the code on how to safely control these modified genes, switching them on and off with the molecular equivalent of a dinner room light switch dimmer.
"The ability to control gene expression in mammalian cells is crucial for safe and efficacious gene therapies and for elucidating gene functions," the scientists write in their paper.
The researchers modified RNA molecules that are meant to produce the needed therapeutic protein that the patient requires, inserting code that's a bit like a "stop sign," the scientists said in a statement. In another part of the RNA molecule, close to the stop sign, they modified a portion of the RNA so it would bind with tetracycline, a FDA-approved antibiotic drug typically used to treat acne.
When that particular RNA portion binds with tetracycline, the stop sign is masked off, so to speak, and the RNA produces the desired therapeutic protein within the patient's body. Take away the tetracycline or reduce the dosage, and the modified RNA will stop making the therapeutic protein or make less of it.
This modification of RNA also sidesteps an issue that has plagued gene expression control: the body often attacks therapeutic proteins as a foreign body.
"Although there are several gene regulation systems used in mammalian cells, none has been approved by the U.S. Food and Drug Administration for clinical applications, mainly because those systems use a regulatory protein that is foreign to the human body, which triggers an immune response against it,” said Baylor medical research professor and the paper's principal investigator Laising Yen in the statement. "This means that the cells that are expressing the therapeutic protein would be attacked, eliminated or neutralized by the patient’s immune system, making the therapy ineffective."
Imagine a future scenario involving a patient with a faulty protein wreaking havoc in their body — perhaps it's cystic fibrosis, which can damage lungs and other body parts through excessive mucus production. Cystic fibrosis can lead to eventually needing time-consuming and expensive therapies for breathing or even new lungs.
At a clinic in the future, the patient could receive a modified RNA targeting the missing or mutated protein causing cystic fibrosis to manifest. Once receiving the modified RNA, which serves as an instructional manual, the patient takes a precise dose of tetracycline to make sure its body is making the correct level of therapeutic protein.
"This strategy allows us to be more precise in the control of gene expression of a therapeutic protein. It enables us to adjust its production according to disease’s stages or tune to the patients’ specific needs, all using the FDA-approved tetracycline dose," Yen said.
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