New Way Of Regulating RNA Expression Could Enhance Gene Therapy

  • A new technique can accurately control the therapeutic protein production once the RNA (Ribonucleic acid) is delivered into cells.
  • This new RNA circuit is built on synthetic biology principles.
  • It will allow doctors to accurately handle patient-specific treatments and rapidly turn off genes in critical situations.

In the medicine field, gene therapy involves inserting one or more ‘modified’ genes into the genetic material of an individual’s cells to treat a genetic disease. It has the potential to revolutionize health care.

Previously, scientists focused on DNA (double-stranded nucleic acid) to deliver genes to damaged cells, but now they are shifting their focus on using RNA (single-stranded nucleic acid), which could provide an easier way to deliver genes with better safety.

In recent years, adeno-associated virus and retrovirus-related gene therapies have shown curative effects in the clinic through long-lasting gene expression. However, transfection (a process of introducing purified nucleic acids into eukaryotic cells) with short-lived nucleic acids would be more suitable for applications that benefit from transient protein expression like cellular reprogramming and gene editing.

Now, the researchers at MIT have developed a new method for regulating the RNA expression once it gets into cells. This enables them to precisely control the protein dose that a patient receives. The technology will allow physicians to accurately handle patient-specific treatments, and rapidly turn off the genes in critical situations.

Designing RNA Circuits

Usually, it’s hard to use DNA for gene therapies. Drugs that are carried by synthetic nanoparticles must be delivered to the nucleus. For DNA delivery, viruses are quite efficient: however, they could be immunogenic, costly, and sometimes they mix their DNA into the cell’s own genome, which limits their suitability in genetic therapies.

mRNA (Messenger RNA) provides a temporary method to change the gene expression of the cell. It transfers copies of DNA information to ribosomes (essential cell organelles) that unite the proteins encoded by genes.

Thus, scientists can deliver mRNA encoding a specific gene to trigger generation of the target protein without integrating genetic material into the nucleus of a cell.

To make this type of gene therapy more efficient, researchers developed a technique to accurately control the generation of therapeutic proteins once the RNA is delivered into the cells. To program RNA circuits, they adapted synthetic biology principles.

These new RNA circuits contain genes for both therapeutic proteins and RNA-binding proteins that control the expression of therapeutic proteins. The performance of the circuit can be configured to enable multiple proteins to express at different times, using a single strand of RNA.

Reference: Nature Chemical Biology | doi:10.1038/s41589-018-0146-9 | MIT

To turn on the circuits at the right moment, one can use nanoparticle drugs that are capable of interacting with RNA-binding proteins. For instance, when doxycycline (FDA-approved) is integrated with cells, it can make the interaction between RNA and RNA-binding protein stable or unstable based on the circuit design.

Such interactions determine whether RNA gene expression is blocked by proteins or not. Researchers have also mentioned that they could develop cell-specificity into the circuits in order to activate RNA in certain cells only.

What’s Next?

Regulating RNA ExpressionConceptual image credit: Noa Alon/MIT

The authors have started a company, Strand Therapeutics, to further develop this technique for cancer immunotherapy – a new treatment approach in which an individual’s own immune system is stimulated to kill tumors.

The team is working on RNA circuits that can carefully stimulate immune cells to kill tumors, which have spread to difficult-to-access body parts. With mRNA, it’s very hard to target cancerous cells like lung lesions due to the risk of inflaming lung tissues. The RNA circuits, on the other hand, will deliver therapy to targeted cancer cells inside the lung, and then it would activate T-cells (via genetic circuitry) that could treat tumor’s metastases.

The circuits will allow physicians to configure dosage based on how each individual is responding. Also, physicians will be able to turn off the production of therapeutic protein if an individual’s immune system gets overstimulated.

Read: New “Molecular Glue” Can Effectively Deliver Drugs To Cancer Cells

In the long term, authors hope to build a more complex system that could be diagnostic as well as therapeutic, meaning identify the problem (like cancer) and then create the necessary drugs for effective treatment.

Written by
Varun Kumar

Varun Kumar is a professional technology and business research analyst with over 10 years of experience. He primarily focuses on software technologies, business strategies, competitive analysis, and market trends.

Varun received a Master's degree in computer science from GGSIPU University. To find out about his latest projects, feel free to email him at [email protected]

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