Senti launches to improve cell therapies with synthetic gene circuits

Senti launches to improve cell therapies with synthetic gene circuits

Building circuits isn’t common in biotech labs, particularly labs developing cell-based therapies for cancer. Tim Lu, who studied computer science and electrical engineering as an undergraduate before going to medical school, wants to change that. But rather than build electronic circuits out of silicon, Lu, now a professor at MIT, is constructing genetic circuits with DNA.

The goal is to design cells that can detect the severity of a disease and release a specific dose of a drug in response. After spending more than a decade developing these genetic circuits in the lab, synthetic biologists Lu, Jim Collins, and Phillip Lee from MIT, along with Wilson Wong from Boston University, cofounded a start-up called Senti Biosciences in late 2016.

Today, they are unveiling the company and announcing that they’ve raised $53 million in series A funding to develop cell therapies for cancer and autoimmune diseases.

Genetically engineering a person’s own immune cells to make them better at fighting cancer is no longer science fiction. The technique is the basis of the first two CAR-T cell immunotherapies commercialized last year. Those launches, along with the approval of the first gene therapy in the U.S., has investors starting to consider cell and gene therapies as a third class of medicines that could rival small-molecule and biologic drugs.

Senti will use genetic circuits to try to improve cell and gene therapy’s precision and limit toxic side effects. For instance, a genetic circuit could be designed to attract a cell to inflammation caused by an autoimmune disease and then release anti-inflammatory drugs in proportion to the degree of inflammation—rather than giving a person a drug that blocks inflammation all over the body. “These features will be really important if we are going to make cell therapies and gene therapies another major wave of medicine,” Lu says.

Senti isn’t providing any specifics about the drug targets or diseases it is working on, but Lu says the output of Senti’s first genetic circuits will be a protein—such as an antibody, cytokine, or chemokine—to treat cancer or autoimmune diseases.

The two commercial CAR-T cell immunotherapies are engineered to target tumors by recognizing a single protein on the cancer cell’s surface, called CD19. Many other CAR-T therapies in development also target a single protein. But often these proteins are found on both healthy and cancerous cells, creating troubling toxicity problems.

In November, Lu’s group at MIT published a study showing that a genetic circuit could trigger T cells to spot and kill cancer cells in mice, while leaving healthy cells alone (Cell ۲۰۱۷, DOI: 10.1016/j.cell.2017.09.049). Senti is building on this work to create a genetic circuit that activates a CAR-T cell, or similar cell therapies, only in the presence of two proteins found on a cancer cell.

“Even a simple increase in sophistication, like sensing two or three antigens, or signatures, before triggering the cell’s activity, is going to make a really big clinical impact,” Lu says.

Genetic circuits may look good on paper, but compared to the physics of electrical or mechanical systems their basic science is still being worked out. “Electrical or mechanical systems are modular. So we can take one component, assemble it with another component, and they work well together. There are no weird interactions that I have to worry about,” Lu says. “But that’s not the case in biology yet.”

Senti isn’t the only company based on genetic circuits. In 2013, Lu and Collins cofounded another company called Synlogic, which is engineering genetic circuits in microbes to create synthetic probiotic therapies. One of Synlogic’s big pharma partners is AbbVie, maker of the arthritis drug Humira, an antibody that blocks an inflammatory protein called tumor necrosis factor (TNF). In theory, engineered microbes could continually release a drug like Humira in response to TNF levels in the body.

Human cells might be better than microbes at homing in on the specific site of inflammation. In fact, Senti recently received a federal grant to develop genetic circuits that allow human cells to sense inflammatory signals like TNF inflammation and locally release anti-TNF drugs in response.

Senti currently has 20 employees. Lu says the series A funding will help double that and also advance several drug candidates through preclinical studies.

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