MIT engineers created a new method to control gene therapy better. They designed a system called ComMAND. This system keeps gene activity within a safe range. They tested it in human cells. The tests showed it could deliver genes for diseases like fragile X syndrome. Fragile X syndrome is a condition causing intellectual disability and developmental issues. The system ensures the gene works at the right level, avoiding side effects.
How ComMAND works
Most gene therapies use a virus to carry the new gene. The virus puts the gene into a cell’s DNA. Some cells get many gene copies, others get none. This leads to uneven gene activity. Too much activity can be toxic. Too little doesn’t fix the problem. ComMAND uses a control circuit called an incoherent feedforward loop (IFFL). An IFFL circuit activates the gene and makes a molecule to limit it at the same time. The molecule is a small RNA piece (microRNA) that binds to messenger RNA, stopping it from making proteins.
In ComMAND, the microRNA is part of the gene. When the gene turns on, it makes both the protein and the microRNA. This balances the gene’s activity. A single DNA promoter controls the whole system. A promoter is a DNA part that starts gene activity. By changing promoters, scientists adjust gene levels. ComMAND’s compact design fits on one virus, making it easier to produce.
The engineers tested ComMAND with genes for fragile X syndrome and Friedreich’s ataxia, a heart and nerve disorder. In human cells, ComMAND kept gene levels safe and effective. Without ComMAND, gene levels were too high, risking harm. Tests in rat neurons, mouse cells, and human T-cells showed similar results. The system precisely controlled a glowing protein gene. Next, scientists will test if ComMAND can reverse disease symptoms in cells or animals. This approach could treat diseases like Rett syndrome or muscular dystrophy.
The engineers have described the methods and results of this study in a paper published in Cell Systems.