Researchers at the Children’s Hospital of Philadelphia have developed a flexible switch that can change the amount of protein produced by gene therapy by triggering different alternative splicing using an oral small molecule drug.
The researchers hope this invention, which was developed in collaboration with the Novartis Institutes for BioMedical Research, can provide gene therapy developers with more control and help tailor therapies better to different conditions.
“Although viral and non-viral approaches for gene therapies have undergone substantial advancement over the past twenty years, the major focus has been on the cargo-delivery system. For example, viral capsid evolution and engineering has improved the cell and tissue targeting of adeno-associated viruses,” write Beverly Davidson, Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and Chief Scientific Strategy Officer at Children’s Hospital of Philadelphia, and co-authors in an article describing the work published in Nature.
“However, the cargo itself—and more importantly the elements that control the expression from that cargo—have not received the same attention.”
It is now possible to deliver therapies effectively to many different tissues around the body, but controlling the amount of protein produced once at the target tissue or organ is more difficult. This can be problematic, as too much of the protein could be toxic to the patient and too little might mean the therapy is ineffective.
Davidson and colleagues sought to address this issue, by creating a splicing modulator switch that they call the Xon system. Using this technology, it’s possible to create a gene therapy that lies dormant in the body until being activated by taking an oral small molecule drug.
“The newly developed switch not only controls protein levels, but if needed, those proteins can be induced again and again by the simple ingestion of an orally bioavailable drug,” said Alex Mas Monteys, an assistant professor in Davidson’s lab at CHOP and co-lead author of the study.
The amount of protein needed can be adjusted by changing the dose of the activation drug, as the researchers showed when they tested their system in mice. They created a therapy to increase levels of erythropoietin to treat anemia associated with kidney disease in a mouse model. The Xon system allowed levels of erythropoietin to be increased by 60-70% after giving the trigger drug. Once levels slowly decreased again the researchers were able to trigger another release of the therapeutic protein.
“The dose of a drug can determine how high you want expression to be, and then the system can automatically ‘dim down’ at a rate related to the half-life of the protein,” Davidson said. “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 research team have yet to test their system in humans, but have high hopes for its efficacy and rollout. They also say it has the flexibility to be used across many different gene therapies and that it could also be combined with CAR T-cells to make a more adjustable immunotherapy.