Laronde Launches to Disrupt the Industry with Programmable Circular RNA Therapies

Since its founding in 2000, Flagship Pioneering, one of Massachusetts’ largest venture capital firms, has launched numerous companies. A remarkable one among them is Moderna, which back in 2012 secured $40 million to transform an innovative idea into life-saving mRNA therapeutics. Flagship has now once again bet on an RNA molecule that it asserts as a new class of medicines.

After four years of working behind the scenes, on May 10th, the Cambridge VC unveiled Laronde, a startup that develops a novel, engineered version of naturally occurring long non-coding RNAs (lncRNAs) called Endless RNA™ (eRNA).

Dr. Diego Miralles, who recently joined Flagship Pioneering as CEO-Partner and has taken over the reins as Laronde’s CEO, is excited about the technology.

“Protein therapeutics are huge in terms of therapeutic modalities like peptides, proteins, and antibodies. However, they are expensive, difficult to make, and cumbersome to administer. With eRNAs, we have a therapeutic tool that is truly a new class of medicine.” Miralles told GeneOnline.

Dr. Diego Miralles

Advantages of eRNA

eRNA is a proprietary, closed-loop RNA construct engineered to be translatable. The technology was invented at Flagship Labs by a team led by Avak Kahvejian, Ph.D., General Partner of Flagship Pioneering, and Founding CEO of Laronde. Speaking to GeneOnline, Dr. Kahvejian shared how his team explored various forms of RNA in the cell and stumbled upon circular RNAs, a possible gold mine.

Circular RNAs are a subclass of non-coding RNAs that lack free 3′ and 5′ ends and naturally exist as closed-loop RNAs. Therefore, these molecules are not recognized by degrading exonuclease enzymes or deemed immunogenic by the innate immune system. This property makes eRNAs ultrastable, enabling a prolonged therapeutic effect.

Unlike mRNAs, these circular lncRNAs do not readily interact with ribosomes. “We were hoping these molecules do a wide variety of things inside the cell, including protein translation. But, it turned out they don’t really translate. Hence, we decided to invent a new format that leverages their stability but can also translate,” Kahvejian said.

Dr. Avak Kahvejian

“We put an internal ribosome entry site, optimized it, and progressively demonstrated its ability to generate prolonged protein expression in vitro and eventually in vivo,” he added.

The years of optimization have led to the eRNA becoming modular and programmable. Switching the eRNA “protein-coding cassette” directs the body to make different peptides, enzymes, antibodies, channels, and receptors, both inside and outside the cell.

In gene therapy, the chronic expression of therapeutic proteins via redosing is a huge challenge. Dr. Miralles pointed out that eRNAs can overcome stability issues and difficulties in prolonged protein expression. Besides, eRNAs exist in the cytoplasm and are not passed down to daughter cells. This enables a transient protein expression, bypassing the dangers of inheritable changes associated with gene editing approaches.

“Now there is a possibility of having access to protein therapeutics through a translatable RNA that is persistent for months and is redosable. This allows one to treat chronic conditions in perpetuity,” Miralles said.

Promising Future

Laronde quite literally means “the round” in French. Flagship has invested $50 million to support the development of its platform and initial pipeline of new medicines. The company also plans to build a modular and scalable eRNA Gigabase Factory to bring to market close to 100 products and drug programs in the next 10 years. To that end, Laronde plans to hire more than 200 people over the next two years.

In recent times, circular RNAs have emerged to be a novel class of medicines. In February, Cambridge-based biotech Orna Therapeutics burst into the scene to advance a new class of circular mRNA therapeutics. With accumulating knowledge of its innumerable benefits, and growing financial backup, circular RNAs are poised to disrupt the industry.

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Author

Rajaneesh K. Gopinath