New technology allows control of gene therapy doses


The feat, reported in the scientific journal Nature Biotechnology, offers gene therapy designers what may be the first viable technique for adjusting the activity levels of their therapeutic genes. The lack of such a basic safety feature has helped limit the development of gene therapy, which otherwise holds promise for addressing genetically based conditions. The scientists' technique appears to solve a major safety issue and may lead to more use of the strategy.

Gene therapies work by inserting copies of a therapeutic gene into the cells of a patient, if, for example, the patient was born without functional copies of the needed gene. The strategy has long been seen as having enormous potential to cure diseases caused by defective genes. It also could enable the steady, long-term delivery to patients of therapeutic molecules that are impractical to deliver in pills or injections because they don't survive for long in the body. However, gene therapies have been viewed as inherently risky because once they are delivered to a patient's cells, they cannot be switched off or modulated. As a result, only a handful of gene therapies have been FDA-approved to date.

The simplicity of the technique, and the fact that morpholinos are already FDA-approved, could allow the new transgene switching system to be used in a wide variety of envisioned gene therapies.

A therapeutic transgene containing the DNA of such a ribozyme will thus be copied out in cells into strands of RNA, called transcripts, that will tend to separate into two pieces before they can be translated into proteins. However, this self-cleaving action of the ribozyme can be blocked by RNA-like morpholinos that latch onto the ribozyme's active site; if this happens, the transgene transcript will remain intact and will be more likely to be translated into the therapeutic protein.

The ribozyme thus effectively acts as an "off switch" for the transgene, whereas the matching morpholinos, injected into the tissue where the transgene resides, can effectively turn the transgene back "on" again—to a degree that depends on the morpholino dose.

The scientists started with a hammerhead ribozyme called N107 that had been used as an RNA switch in prior studies, but they found that the difference in production of a transgene-encoded test protein between the "off" and "on" state was too modest for this ribozyme to be useful in gene therapies. However, over months of experimentation they were able to modify the ribozyme until it had a dynamic range that was dozens of times wider.

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