Precise Gene Therapy Control

MIT engineers have designed a new method to improve the precision of gene therapy treatments by using gene circuits that regulate gene expression levels. 

Gene therapy has long been seen as a promising solution for diseases caused by missing or defective genes, such as hemophilia and sickle cell anemia. However, only a few treatments have received FDA approval due to challenges in controlling gene expression—too little expression makes the therapy ineffective, while too much can cause harmful side effects.

MIT’s new approach addresses this issue with a control circuit that ensures precise regulation of gene expression within a desired range. By fine-tuning this circuit, the researchers could improve treatment for conditions like fragile X syndrome, which causes developmental and intellectual disabilities.

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Katie Galloway, Senior Author and MIT Professor, notes, “Gene supplementation can solve monogenic disorders, but success depends on precise control of expression levels.”

The Power of Gene Circuits

Traditional gene therapy uses viruses to deliver genes into cells, but varying gene uptake can lead to inconsistent expression, complicating treatment. MIT researchers tackled this with an incoherent feedforward loop (IFFL) circuit that activates the target gene and simultaneously produces a microRNA to suppress its expression, allowing precise control.

Their system, ComMAND (Compact microRNA-mediated Attenuator of Noise and Dosage), uses a single promoter to regulate gene expression. This compact design fits on a standard gene delivery vehicle, improving manufacturability.

The team demonstrated ComMAND’s effectiveness by delivering genes for Friedreich’s ataxia and fragile X syndrome, achieving precise regulation—up to eight times normal expression levels—compared to uncontrolled overexpression in previous methods.

This innovation offers more reliable gene therapy, particularly for rare genetic disorders like Rett syndrome and muscular dystrophy, where small patient populations make precise control vital. As Galloway notes, “We’re developing tools like ComMAND to make treatments more feasible for these conditions.”