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Aiming for on/off switch of genes, Chroma corrals $125M for new wave of medicines

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Cells have the same DNA, but the body has a built-in way to effect what any given cell becomes, whether it’s a liver cell or a neuron. That system, called the epigenome, takes what is in the DNA and makes sense of it, explained Catherine Stehman-Breen, CEO of biotech startup Chroma Medicine. If you think of DNA as hardware, then the epigenome is the software that tells the hardware what to do, she said.

Genetic medicines research is marching forward with therapies that treat disease by cutting and editing the genome, or by introducing genetic material intended to fix faulty genetic code. But Stehman-Breen said tapping into the epigenome offers an alternative approach, and one with potential advantages. Instead of trying to correct a mutated gene, Chroma is targeting the software that controls it in order to regulate its expression.

“Leveraging this mechanism allows us to have a tremendous amount of breadth in terms of therapeutic application,” Stehman-Breen said. “We think it’s ultimately a really powerful tool.”

Cambridge, Massachusetts-based Chroma is building a pipeline of epigenetic medicines that turn genes on or off and the startup has raised $125 million to support its research. The Series A round of funding announced Wednesday was led by Cormorant Asset Management.

Chroma’s approach mimics what the body already does, said Vic Myer, the company’s president and chief scientific officer. There are some genes, such as retroviruses in the genome, that remain dormant for life because the epigenome turns them off. Similarly, a Chroma drug would silence a toxic or mutant gene, allowing a healthy gene to do its job. For haploinsufficiencies, diseases in which one gene of a gene pair is not functioning properly, Chroma would take the opposite approach and turn on gene expression.

The drugs themselves are large molecules engineered to go to a specific location in the genome, Myer said. The goal is for these therapies to be one-time treatments. After the drug does its work, when the cell divides, the epigenomic system understands that a particular gene is supposed to be turned off. The daughter cells that follow retain the gene silencing. Myer, a former executive at gene-editing biotech Editas Medicine, said he left that company after nearly five years wanting to do something different. He was persuaded to return to genomic medicines by Chroma’s technology.

“It’s an elegant approach, and sort of a natural, normal approach to turn off a gene if you want to turn off a gene, and turn on a gene if you want to turn on a gene,” Myer said.

Chroma is based on the research from its six scientific founders: Luke Gilbert, Keith Joung, David Liu, Angelo Lombardo, Luigi Nadine, and Jonathan Weissman. According to Stehman-Breen, the basis of Chroma was research from Weissman, Gilbert, and others, published in the journal Cell in 2016, showing how a “CRISPRoff” fusion protein could turn off gene expression. That change was maintained as cells divided and as stem cells differentiated into neurons.

Chroma, which formed last year, recently acquired Milan, Italy-based Epsilen Bio, whose co-founders include Lombardo and Naldini. Stehman-Breen said Chroma’s founders knew Lombardo and Naldini, and ongoing conversations led the founders to conclude that the two companies are complementary, and it made sense to pursue epigenetic medicines together.

Gene silencing is the most advanced part of Chroma’s technology platform. Myer said that’s because silencing is absolute—when you turn a gene down, it’s hard to turn it down halfway. Turning on a gene can have a different set point for gene expression. From a therapeutic perspective, Chroma’s research into turning on a gene “is a bit further out,” Myer said.

The idea of silencing a gene might be most recognizable as the approach taken by RNA interference (RNAi). These nucleic acid therapies activate a mechanism already in cells that stops a gene from producing a disease-causing protein. Alnylam Pharmaceuticals won first FDA approval for an RNAi therapy. But an RNAi’s therapeutic effect does not last, so these treatments must be taken chronically.

There are other approaches to regulating gene expression. Constellation Pharma’s clinical-stage epigenetic medicines are small molecules that target enzymes that activate or inactivate disease-causing genes. That biotech, whose research focuses on cancer, was acquired by MorphoSys earlier this year for $1.7 billion. CAMP4 Therapeutics is developing programmable RNA therapies intended to upregulate gene expression to address haploinsufficiencies. Cambridge-based CAMP4 raised $45 million in June.

Omega Therapeutics, a Flagship Pioneering-founded biotech that went public in July with a $126 million IPO, is developing therapies it calls “epigenomic controllers.” These fusion proteins are designed to target insulated genomic domains on DNA. But rather than the binary approach of turning genes on or off, the Cambridge company more precisely “tunes” a therapy up or down to the right level of gene expression, and for the right duration. Omega’s lead therapeutic candidate regulates a tough-to-target gene whose activity is linked to the progression of numerous cancers. Tuning down rather than turning off the gene is the best approach because healthy cells also rely on the gene, CEO Mahesh Karande explained to MedCity News earlier this year.

Chroma isn’t yet disclosing the diseases it aims to treat. Stehman-Breen said the $125 million sum represents the total that the company has raised since its inception. She estimates the cash will last for the next two years as the startup continues to build the technology platform and develop new therapies.

Other investors in the financing included Casdin Capital, Janus Henderson Investors, Omega Funds, funds and accounts advised by T. Rowe Price Associates, and Wellington Management, along with seed investors Atlas Venture, Newpath Partners, and Sofinnova Partners.

Photo by Flickr user Dean Hochman via a Creative Commons license

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