MIT team designs gene circuits for tighter control in gene therapy study

An MIT research group has unveiled a set of synthetic gene circuits designed to give scientists more  control over gene-therapy treatments, according to a recent paper. The study, appearing in the journal Cell Systems, describes genetic constructs meant to fine-tune how and when therapeutic genes are switched on inside a patient’s cells, aiming to keep expression levels within a specific target range and potentially aiding treatments for diseases like Fragile X syndrome.

The abstract notes that the researchers “experimentally tuned the ComMAND output profile” and used modeling to explore further adjustments. They demonstrated the “precise control afforded by the single-transcript architecture,” especially compared to other designs when gene delivery is low. This system effectively keeps levels of “clinically relevant transgenes” like FXN (frataxin) and Fmr1 “within a narrow window,” making it a “compact tool” for controlling therapeutic gene expression.

MIT also announced the news in a press release.

Lead author Katie Galloway, the W. M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering at MIT, worked with graduate students Kasey Love, Christopher Johnstone, Emma Peterman and Stephanie Gaglione on the project. Associate Professor of Biological Engineering Michael Birnbaum is a co-author.

‘Gene circuits’

The team’s approach centers on “gene circuits,” engineered DNA sequences that can be programmed to regulate other genes. Specifically, they developed a type of circuit called an ‘incoherent feedforward loop’ (IFFL), named ‘ComMAND,’ which uses microRNA produced alongside the therapeutic gene to automatically limit its expression. By integrating those circuits into standard gene-therapy vectors, the researchers aim to tighten control over dosage. The approach also helps address the challenge where uncontrolled delivery can lead to levels that are too low to be effective or dangerously high. Love, Johnstone, Peterman and Gaglione constructed and tested the circuits under Galloway’s direction. Birnbaum provided additional oversight on biological-engineering aspects of the work.

The MIT group reports that their circuits can be tuned using different genetic ‘switches’ (promoters) to adjust the target expression level. They say that  this compact, single-transcript design is suitable for common viral delivery vectors and could let clinicians adjust therapy parameters without rebuilding an entire vector from scratch.

Potential for a range of disorders

The authors write that the technique could eventually be applied to a range of disorders now being investigated for gene therapy, having demonstrated its function in human cells using genes relevant to Friedreich’s ataxia and Fragile X syndrome. The ability to dial gene activity up or down, they add, may help researchers address safety concerns that arise when therapeutic proteins are overproduced; in their cell tests, the circuit constrained expression to moderate levels (e.g., about 8x normal), preventing the much higher, potentially toxic levels (e.g., >50x normal) seen without the control system.

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Filed Under: Cell & gene therapy
Tagged With: gene therapy
 

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