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Endpoints: Bayer backs a George Church spinout trying to turn lab-invented amino acids into a new class of protein therapies

By November 3, 2021November 5th, 2021No Comments

Six years ago, Daniel Mandell appeared on NPR to talk about an invention out of Jurassic Park.

As Crichton and Goldblum fans recall, International Genetic Technologies, Inc.’s contingency plan to make sure dinosaurs didn’t escape was to take away their ability to make the amino acid lysine, forcing them to rely on lysine supplements from the park staff for survival.

Mandell, a fellow at George Church’s Harvard lab, took the idea a step further. He, Church and a team of scientists engineered a bacteria dependent on an artificial amino acid that didn’t exist anywhere; scientists had invented it.

In theory, you could exploit that reliance to make sure genetically engineered organisms didn’t spread outside their intended use. For example, you could use the modified bacteria to clean up an oil spill and then get rid of the bacteria.

“While lysine is a natural amino acid that is found everywhere in nature,”

Mandell explained on Science Friday,

“our amino acid exists only where we put it.”

Their bacteria never deployed to clean up oil spills, but that was only one in a long list of potential applications for an organism that can rely on and churn out artificial amino acids. And after years of fine-tuning and industrializing the academic bacteria, Mandell has managed to raise money from blue chip investors to use his organisms elsewhere: building new kinds of therapeutics.

On Wednesday , GRO Biosciences, the company he co-founded shortly after the original work appeared in Nature, announced a $25 million Series A led by Leaps by Bayer and Redmile Group to develop therapies with artificial amino acids. The new round adds to earlier seed cash from Digitalis and Innovation Endeavors, former Google CEO Eric Schmidt’s VC.

Amino acids are the basic building blocks of proteins, so it’s perhaps unsurprising that GRO will focus on protein-based therapies. Only 20 amino acids occur in nature, each coming together in various sequences and conformations to form the proteins that make up all life.

By adding new types of amino acids, Mandell and his CSO and co-founder Christopher Gregg — and a long list of academics and a few biotechs,including the $2.5 billion Sanofi subsidiary Synthorx — think they can make proteins with new properties.

“As a designer, one is often struck by a fundamental limitation of proteins, which is that they’re all comprised of the same 20 amino acid building blocks,”

Mandell, now CEO, said in an interview. Adding new amino acids “really opens up an incredibly exciting chemical universe.”

GRO claims that its advantage will come from its synthetic organisms. It can be difficult to get bacteria to manufacture these artificial building blocks; picture a factory trying to put together a car from misshapen parts.

GRO can make bacteria that are not only reliant on synthetic amino acids to survive, but Mandell said, are also uniquely adept at churning out proteins with synthetic amino acids.

“All this leads to very high efficiency, production and scalability,”

he said.

The first approach is the most intuitive. GRO will try to use the artificial amino acids, technically known as non-standard or non-canonical amino acids, to build therapeutic proteins that can last longer than current protein-based therapies.

Numerous metabolic diseases can be treated by giving patients artificial versions of a human protein: replacements for enzymes patients with genetic disorders such as Fabry disease are missing, or various treatments for diabetes. These drugs, though, often have to be dosed weekly or even daily.

It’s “onerous,” Mandell said. And it “causes non-compliance in patients.”

In theory, GRO’s proteins can be infused and remain in the body at roughly the same concentration for an extended period. That would both ease dosing and prevent the big spike and decline in protein levels patients often see.

The second approach involves autoimmune diseases. Synthetic amino acids can also be used to create proteins with different so-called post-translational modifications — i.e. the various decorations and accoutrements that cells often place on top of proteins to serve different functions.

Coronaviruses, for example, use a coat of sugary molecules called glycans to shield themselves from the immune system. Glycans, though, can also be used to train the human immune system.

In an autoimmune disease like multiple sclerosis, a patient’s immune cells begin attacking myelin proteins in their nervous system. By giving that patient lab-made myelin proteins studded with the right glycan coat, GRO hopes to coax the immune system to learn to tolerate myelin again.

Neither of these ideas are entirely unique to GRO, although synthetic amino acids have mostly been used in the past for conjugation.

The company, though, is still in its early stages. They plan to put their first therapies in the clinic in 2024, while also developing new microbes that potentially can build proteins with multiple artificial amino acids, allowing for further design.

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