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Engineering the Microbiome – the Next Frontier

Microbiome Futures Roadmap

Microbial ecology, our understanding of what determines the robustness and community dynamics of microbial consortia, and synthetic biology, the art of engineering microorganisms to perform particular physiological or metabolic functions, are rapidly becoming allies in the race to develop novel therapeutic strategies in the microbiome space.

“Exciting research into additive, subtractive or modulatory strategies for affecting human health through the human microbiota is being powered by advancements in synthetic biology and microbial ecology,” says Tim Lu, head of the Synthetic Biology Group at the Massachusetts Institute of Technology. “In my view, engineered microbes that can sense and remedy disease by producing therapeutic molecules or degrading toxic metabolites in situ, are on the horizon.” Lu is a co-founder of microbiome plays Synlogic, Inc., BiomX Ltd., and Eligo Bioscience.

Comparably few companies are dipping into this opportunity, but some of them are doing so with gusto and with the investor backing to show for it. Just two weeks ago we saw Paris-based Eligo Bioscience secure a USD 20 million Series A round of financing from Khosla Ventures and Seventure Partners. And in late August, Cambridge, MA, based Synlogic, Inc. closed a reverse merger with Mirna Therapeutics, Inc., which netted the company USD 40 million (and greater access to additional capital through its NASDAQ listing), after it had earlier in the year already secured a USD 42 million Series C round of financing. Also on the East Coast, Farmington, CT, based Azitra Inc. announced in April the closing of a USD 2.9 million Series A round of financing led by Bios Partners.

These companies, all founded in 2014, have taken three very distinct tacks on the opportunity of merging microbial ecology and synthetic biology.

In the case of preclinical-stage Eligo, the company is developing so-called eligobiotics, a bacteriophage-based platform designed for the targeted delivery of customized therapeutic payloads to bacteria of interest in a microbiome. In its first incarnation, eligobiotics have been engineered to deliver a CRISPR-based genome editing payload to pathogenic bacteria in the gut microbiome. When they encounter a target bacterium, the CRISPR eligobiotics get to work destroying the bacterial DNA beyond repair, effectively killing the target organism. The surrounding microbiome, however, is left untouched and ready to reestablish its healthy balance.

By contrast, Synlogic has taken a more classical approach: genetic reprogramming of probiotic bacteria to treat rare metabolic diseases as well as inflammatory diseases and cancer. The reprogrammed bacteria not only produce a metabolite or two of interest but also harbor detection systems and other safety controls to function as true smart and safe drugs. These so-called Synthetic Biotic medicines have already entered the clinic, with the company’s lead product for hyperammonemia, SYNB1020, now being evaluated in a Phase 1 trial. In the first half of 2018, Synlogic expects to initiate clinical trials with SYNB1618, a second Synthetic Biotic medicine candidate for the treatment of phenylketonuria.

And just like Synlogic, Azitra is developing recombinant probiotic bacteria, but in this instance, the focus is on the skin. Safe skin bacteria are reprogrammed to produce therapeutic proteins of interest to be delivered directly into the skin. These recombinant strains are then applied topically using a cream. The company’s lead candidate, AZT-01, is a Staphylococcus epidermidis strain expressing filaggrin, a protein defective in patients with eczema. Using an engineered human commensal bacterium to deliver therapeutic proteins to the skin could be a ticket to creating innovative and inexpensive treatments for skin diseases ranging from eczema to staph infections.

Two other synthetic biology players in the skin microbiome space are Redwood, CA, based Topgenix and San Diego, CA, based Xycrobe Therapeutics Inc.

Topgenix is developing a platform using probiotic bacteria to express compounds of interest for delivery to the skin. The first application is a skin lotion containing bacteria that produce a UV-protective compound. And Xycrobe is engineering commensal skin bacteria to penetrate the top layer of dead skin cells to deliver beneficial compounds such as antioxidants and anti-inflammatory molecules.

Rounding up the intersection of synthetic biology and the microbiome are three more companies.

San Francisco-based Blue Turtle Bio is developing engineered gut microbes to treat rare diseases caused by protein deficiencies. The company’s first product is a microbial strain that secretes glucocerebrosidase, an enzyme that could help treat Gaucher’s disease. The bacteria, delivered in the form of a time-release pill, could prove to be an economical alternative to costly intravenous drugs.

Osel Inc., a Mountain View, CA, based company with a track record of developing live bacterial therapeutics, all based on naturally existing bacteria for women’s health and disorders of the gastrointestinal tract, has started exploring the potential for using engineered bacteria through its MucoCept platform, a modified Lactobacillus expressing a potent anti-HIV-1 antibody fragment.

Finally, Intrexon Inc., a Germantown, MD, based company is developing ActoBiotics, engineered Lactobacillus for oral delivery of therapeutic proteins and peptides. Clinical stage ActoBiotics include AG013 for oral mucositis and AG014 for inflammatory bowel disease.

The intersection of synthetic biology and microbial ecology promises to be one of the leading edges in innovation in the microbiome space. With few companies dipping into the fray as of yet, the picture emerging is one of opportunities in many different therapeutic areas — from skin to gut — and with different modalities —phage-based antimicrobials to bacterial-based replacement therapies.

The primary goal in all instances is to harness our knowledge of microbiome dynamics and use the synthetic biology toolbox to trigger a rebalancing act in the resident microbial flora.

Microbiome Futures 2018-Global Engage
Gaspar Taroncher-Oldenburg
 is Consultant-in-Residence for Global Engage. He was previously Founding and Managing Editor of Nature’s SciBX: Science-Business eXchange (now BioCentury Innovations) and scientific editor of Nature Biotechnology.

 

Look at who will be taking part in Microbiome Futures: A Global Translational Roadmap.

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