The story of how genes are regulated has gotten a whole lot more complicated in recent years. Scientists, using ever-improving sequencing technologies, are discovering the many ways the cell can turn gene activity up or down. With this growing insight comes an expanding list of potential drug targets and biotech startups that are going after those targets. The latest addition to that list, Accent Therapeutics, today announced a $40 million Series A financing round from The Column Group, Atlas Venture and EcoR1 Capital.
The Cambridge, MA-based company is in the earliest stages of drug discovery, and is betting on some really new science. Only in the last five years or so have scientists started learning the details of yet another method of gene regulation—chemical changes at the RNA level. RNA, in particular messenger RNA (mRNA), is important because these molecules are made based on the DNA code and provide the instructions for making proteins to the cell’s protein-making machinery. But before the cell makes proteins from RNA, it harnesses a variety of enzymes to attach or remove chemical groups from the RNA. These chemical modifications don’t affect the sequence of the RNA molecule, but they do change the RNA’s molecular structure, stability and function. This can ultimately affect how much protein is made from a particular mRNA. This gives the cell another control knob to turn when it wants to fine-tune the activity of a gene.
These discoveries have opened up a new field of research, called (brace yourself) “epitranscriptomics.” The first maps of the human epitranscriptome (showing the sites along mRNA that have certain chemical modifications) emerged only in 2012, and scientists are still figuring out the biological effects of many of these chemical tags. Researchers think they are important for cell and embryonic development—the kinds of cellular processes that can go awry in cancer. Indeed, some early research has already implicated a few RNA-modifying enzymes in cancer.
Even if the science is still early-stage, it was enough to convince Bob Copeland to co-found a company. “I like working on the cutting edge of new biology,” says Copeland, who is Accent’s president and chief scientific officer. But being on the cutting edge also means there’s a lot of work that lies ahead for Accent. The company aims to find small molecule drugs that inhibit RNA-modifying enzymes and other proteins that are involved in cancer. The idea is that cancer cells might be relying heavily on these enzymes to make biochemical changes that eventually drive hyper cell growth.
Now it’s up to the Accent team to find the RNA-modifying enzymes that are most relevant in cancer. To do this, Copeland says his group is using, among other tools, a CRISPR-based system that allows them to systematically knock out genes involved in RNA modification one by one, in a wide range of cancer cell types. Copeland says his company has already found around 20 targets and prioritized four that they’re moving ahead with. The plan is to keep finding more.
Eva Maria Novoa, an epitranscriptomics expert at the Garvan Institute of Medical Research in Sydney, Australia (who’s not involved with the company), says there are a lot of unknowns about the biology of RNA modification. For example, for many RNA changes, we still don’t know which enzymes are responsible for making those changes, she says. And an association initially found between a specific mutation in a RNA-modifying enzyme and a disease doesn’t always pan out after further research. But she remains optimistic about the therapeutic potential. Pursuing “RNA modifications as drug targets is ambitious, yet feasible,” says Novoa.
Copeland is not new to startups. He started at Epizyme in 2008 as its first CSO and fourth employee. He spent nine years there as the company grew, went public, and took three drugs into clinical testing. Epizyme is developing small molecule “epigenetic” drugs that inhibit enzymes involved in chemically altering DNA. Copeland says there are some similarities in how epigenetic and epitranscriptomic drugs work, but there’s a key difference. He thinks that by targeting RNA modifications (as opposed to DNA ones), epitranscriptomic drugs will hopefully be more precise in regulating the production of a disease-related protein, because RNA is closer to protein function than DNA.
Accent’s other cofounders are Chuan He, a researcher at the University of Chicago who has made a lot of the basic discoveries in the field; and Howard Chang of Stanford University, who has done work on RNA, gene regulation, and cancer.
Copeland is not saying which types of cancer Accent is pursuing, or when his 10-person company will be in the clinic, but he says he’ll likely need more funding to take his first drug candidate into human testing.
The arrival of Accent is another sign of the surging interest in targeting RNA with small molecule drugs. “There’s a renewed appreciation for the central role of RNA in so much of biology,” says Copeland. “RNA sits at the crossroad of genes and proteins and there’s more recognition of its medical significance.”