Precisely targeting liver cancer with logical gene therapy


Several small molecule drugs and immunotherapies have been approved for liver cancer. But the lack of response in some patients and the potential side effects point to the need for new treatments. Today, a Swiss team has designed a gene therapy which, by processing multiple cellular indices, precisely targets liver cancer in mice.

Borrowing a concept from calculus, scientists at ETH Zurich have created genetic “logic gates” that can differentiate tumor and non-tumor cells based on their molecular profiles. Gene therapy using the system, combined with the antiviral drug Cytovene by Roche (ganciclovir), significantly reduced tumor burden in mice with hepatocellular carcinoma, the most common type of liver cancer, while sparing organs healthy, according to results published in Science Translational Medicine.

The study authors co-founded a startup called Pattern BioSciences based on biomolecular computational technologies like this one. The aim is to advance new therapies for liver cancer with improved specificity and safety over existing options, said Yaakov “Kobi” Benenson, lead author of the study and co-founder of the spin-off of ETH Zurich, to Fierce Biotech Research by e-mail.

Although targeted therapies are available for cancer, these targets are rarely perfectly unique to cancer cells. The ETH Zurich team believed that integrating logic gates, which can process different molecular inputs and act accordingly, could improve the accuracy of cancer therapy.

Cancer cells in the liver express the transcription factors HNF1A and HNF1B, and they also overexpress the tumor-associated SOX9 and SOX10 transcription factors. The team has developed an AND gate that can trigger therapeutic action when HNF1A / B and SOX9 / 10 are present in a cell.

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But some healthy liver cells also express SOX9. To improve targeting accuracy, the team added a NOT gate to shut down the system when it encounters microRNA that is highly expressed in healthy cells but not in tumor cells.

After several rounds of screening and testing, the researchers opted for let-7c. MicroRNA showed a substantial difference in activity between healthy liver cells and liver cancer cells and it was also found to be highly active in all other organs.

For the final product, the researchers linked the logical gates to a herpes virus gene called HSV-TK. If a cell successfully crossed both gates, it would trigger the production of the HSV-TK protein, which can convert Cytovene into a cytotoxic compound. The whole system was packaged in gene therapy based on adeno-associated viral vectors.

In mice with liver cancer, treatment dramatically reduced tumor burden, while control animals treated with placebo, the vector encoding the complete biometric system alone or Cytovene alone showed exponential tumor growth, the researchers reported. Therapy with only the AND gate and Cytovene resulted in a strong antitumor effect, but the treated rodents rapidly lost body weight as their general health deteriorated. By comparison, the mice that received the full therapy experienced no apparent side effects.

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Logically triggered gene circuits have sparked interest in cancer research because of their ability to simultaneously track down multiple targets that can process differences between tumor cells and their promise to avoid high toxicity. California-based biotech Senti Bio just reported positive mouse data for its SENTI-202 logic-triggered CAR-NK cell therapy, which is designed to target acute myeloid leukemia cells expressing FLT3 or CD33, while sparing healthy cells thanks to the recognition of the endomucin protein.

For Pattern BioSciences, the company plans to launch a first human study in 2025 for its logic gene therapy. The Swiss startup aims to build a biomolecular computing platform, using multi-omic data to select targets for the design of logic gates, said Benenson.

The company’s initial focus is liver cancer, but it is also exploring partnership opportunities to expand the technology to other indications such as central nervous system and inflammatory diseases, he added. The company has raised angel investments and attracted research funds from the Swiss innovation agency Innosuisse, among others.


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