Each year, a growing number of patients benefit from cutting-edge “biologic” drugs, complex proteins designed to ease hard-to-treat conditions ranging from rheumatoid arthritis, to Crohn’s disease, macular degeneration, cancer and more. While effective, they can be expensive to make, highly perishable, and must be administered via injections or intravenous infusions.

CU Boulder biochemistry professor Robert Batey and Alexandria Forbes, Ph.D., founder and CEO of New York-based biotech firm MeiraGTx, imagine a better way: One day, they believe, next-generation gene therapies could be used to nudge the body’s own cells to make those proteins at precisely the right time and in just the right amount.

Now, they’re teaming up to explore how to do it.

“Our ultimate aim is not only to be able to put genes into cells of patients to produce therapeutic proteins, but also to be able to switch those genes on and off,” using oral or topical medications, says Forbes, who enlisted Batey to help refine the switch.

For example, instead of getting an IV every two weeks for arthritis, a patient could get one treatment to insert the gene and then take a pill every two weeks to switch it on. Instead of having an injection in the eye every month for the treatment of a blinding eye disease, they could use an eye drop that activates cells in the eye to produce their own remedy.

These are early days in the research, Batey stresses. “But there are a whole host of diseases that could be targeted using this regulated gene therapy approach.”

Gene therapy 101

Still largely an experimental approach, gene therapy has primarily been tested in the context of inherited genetic diseases, explains Forbes, whose firm is involved in several clinical trials looking at gene therapy for rare, inherited eye diseases. The protein-coding sequence of a gene is introduced into a cell to replace a defective or mutated gene. In some cases, it might be OK for the healthy replacement gene to remain “switched on.”

In others, having the gene “on” all the time could be detrimental.

“Most genes respond to signals and are only on some of the time,” explains Forbes. “If we are able to switch our therapeutic genes on and off, it significantly broadens the potential application of gene therapy.”

The company has already developed a suite of novel dimmer switches, which can modulate gene expression. Now the challenge is to develop switches that are inherently tuned to respond to specific small molecules, or drugs, that flip the switch.

That’s where Batey comes in.

Making a better switch

Since 2004, Batey has been studying the structure of ribonucleic acid (RNA) – the genetic messenger that, among other functions, tells the cell to ramp up or pull back on production of enzymes or proteins. More recently, he has focused on aptamers – sequences of RNA that fold into complex shapes that serve as instructions to recognize certain pre-selected small molecules and respond to them.

Scientists have been developing synthetic aptamers for decades, but only a few have been successful in cells or as therapeutics, notes Batey. That’s in part because they tend to misfold upon entering the cell, losing their instructions in the process.

Batey’s lab has been observing how natural aptamers found in bacteria work. The aim is to come up with a better artificial aptamer design that retains its structure inside the cell.

In January, he and his colleagues published a paper n Nature Chemical Biology showing they could develop an aptamer that recognizes and binds to 5-hydroxy-L-tryptophan (5HTP), a small molecule already commonly found in dietary supplements.

Ultimately, that same method could be used to develop aptamers that could sense and respond to a whole host of pre-selected compounds, flipping the genetic switch accordingly when they’re present.

“Rob is one of the world’s experts in how to select and design aptamers that bind to small molecules,” said Forbes, who reached out to Batey after reading one of his papers.

Working with CU Boulder’s Technology Transfer Office (TTO), Batey recently licensed a patent-pending technology for aptamer selection to MeiraGTx for use in gene therapy, and forged an agreement to work with them on further research. MeiraGTx in turn will help fund Batey’s work.

“This is a great example of open innovation – collaboration that starts in the early stages and goes in both directions, allowing everyone to benefit from a broad range of skill sets,” says TTO Director Bynmor Rees.

In 2009, Batey was named Inventor of the Year by the TTO office after licensing some of his other inventions to BioRelix Inc., a company developing novel compounds for fighting drug-resistant pathogens.

While he has licensed his aptamer-development technology to MeiraGTx for gene therapy, he notes it could also hold promise as a tool for diagnosing disease.

“We are just at the beginning of a new era in the lab, exploring several different avenues for these small molecule aptamers that could be passed off to companies or academic users,” Batey says.