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Fine-Tuning Process Devised for Gene Therapies

Gene therapy graphic

(Genome Research Limited, Flickr)

29 July 2021. Researchers designed a technique to adjust the volume of proteins from gene therapy released into patients, providing more control for complex diseases. A team from Children’s Hospital of Philadelphia and drug maker Novartis reported their findings yesterday in the journal Nature (paid subscription required).

Gene therapies, where healthy or edited genes are transferred into patients with damaged or mutated genes, are being designed and tested for treating inherited disorders. These treatments are delivered with engineered benign viruses or lipid nanoscale particles, but once into patients’ cells, there’s little control over the amount of protein expression from the delivered genes. Too much of the proteins released can harm some patients, say the authors, while too little protein delivery can mean inadequate benefit for patients.

To provide more control over gene therapies, researchers from the lab of Beverly Davidson that studies genetic diseases in children devised a process for chemically adjusting levels of protein expression higher or lower, much like a dimmer switch on a light. Their process uses a technique called RNA splicing, where RNA expressed from the DNA genetic code is edited or spliced to add or remove non-coding regions called introns in the DNA. The remaining sequences, expressed in RNA, are synthesized in cells to produce proteins at varying levels depending on the RNA splices.

Adjusting protein expression up or down

The team, including staff from Novartis Institutes for BioMedical Research, designed the process to activate gene therapies after taking a small molecule drug that carries splicing instructions for the healthy or corrected replacement genes. The process, called Xon, can adjust the extent of protein expression up or down as needed. Xon also allows for repeated dosing from the delivered genes if required.

The researchers tested Xon in lab mice using delivered genes expressing the hormone erythropoietin, produced in the kidney. People with chronic kidney disease can produce too little erythropoietin, resulting in too few red blood cells and anemia. The team found by adjusting doses of the drug using Xon techniques can adjust genes expressing erythropoietin to increase red blood cells 60 to 70 percent above baseline levels. Moreover, the researchers show they can reactivate expression of erythropoietin to induce repeated doses of the hormone.

“The dose of a drug can determine how high you want expression to be,” says Davidson in a Children’s Hospital statement, “and then the system can automatically ‘dim down’ at a rate related to the half-life of the protein. Davidson adds, “We can envision scenarios where a drug would be given only once, such as for controlling the expression of foreign proteins needed for gene editing, or with limited frequency. Since the splicing modulators we have tested are given orally, compliance to control protein expression from viral vectors employing Xon-based cassettes should be high.”

The researchers say Xon techniques can also be used with engineered T-cells, such as those with chimeric antigen receptors or CAR T-cells given as cancer therapies. Novartis licenses the Xon technology, patented by Children’s Hospital with Davidson as inventor.

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