New research at the Scripps Research Institute made a revolutionary development of a special molecular switch that can be embedded into gene therapy and will help in controlling doses. The first viable technique which will help the gene therapy designers in adjusting the activity levels of therapeutic genes.
The study results are published in the journal “Nature Microbiology”
The lack of this basic safety feature has limited the development of gene therapy which will otherwise aid in addressing genetically based problems. This revolutionary technique will solve major safety issues and may lead the basis for the development of new strategies.
The research team was led by the principal investigator, Michael Farzan., who showed the power and efficacy of this new switching technique by incorporating this into a gene therapy that produces the erythropoietin hormone, used for anemia treatment.
They demonstrated the suppression gene expression to a very low level with the help of a special embedded molecule and also showed the increase of its expression over a wide range by using injected control molecules; morpholinos which are considered safe also for other applications by the U.S. Food and Drug Administration.
Gene therapy works by inserting a copy of the therapeutic gene into the cells of patients, for instance, if the patient was born without the functional copies of the required gene. This strategy is the potential for the treatment of diseases caused by faulty genes.
It enables the long term steady delivery of therapeutic molecules to the patients that are not possible to deliver in the pills or in injections because of their short survival. But gene therapies are inherently risky because they can’t be modulated or switched off once they are delivered to the cells of the patients. So, FDA has approved only a handful of gene therapies.
Morpholines are FDA- approved. The simplicity of this technique and its approval by the FDA could permit the new transgene switching system to be used in a vast variety of gene therapies.
The team including the study co-first authors Haimin Wang and Guocai Zhong,, respectively a research assistant in the Farzan Lab and a postdoctoral researcher made a transgene switch from ribonucleic acid (RNA) molecules known as hammerhead ribozymes. These ribozymes have unusual property they divide themselves in two as early as they are copied out from the DNA into RNA.
The copied strands of RNA are called transcripts that will get separated into two before protein translation. The self-cleaving action of the ribozyme can be stopped by the morpholinos that will latch on to the active sites of the ribozyme. As a result, the transgene transcript remains intact and will translate into the therapeutic protein.
The research team demonstrated the ribozyme-based molecular switch in a mouse model of an EPO gene therapy. It isn’t FDA approved but considered potentially much better than the current models for the treatment of anemia linked with severe kidney diseases. The team injected an EPO transgene in muscle tissue of live mice and demonstrated that the suppressed EPO production to an extremely low level by the embedded ribozyme.
Small dose injections of morpholino molecules into the affected tissues reversed the suppression and showed increased EPO production by the factor above 200 and stay continued for more than a week as compared to the half-life of few hours for EPO which is delivered by the standard injection. These properties make the molecular switch potentially suitable for clinical applications.
Researchers are now working for adapting the ribozyme-switch for using it as a gene therapy failsafe method, deactivating the stray transgenes permanently.