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“Turning down the volume” of a faulty gene in heart disease

Scientists at Stanford use a gene therapy technique, called RNA silencing, to treat a heart condition called restrictive cardiomyopathy in mice.

Twelve years ago, then-assistant professor of cardiovascular medicine, Euan Ashley sat in his new office, contemplating an idea.

Part cardiologist, part geneticist, Ashley, D.Phil, FRCP, was mulling over potential ways to repair faulty heart cells from a heart with a condition called cardiomyopathy, which inhibits the heart's blood-pumping ability. He was considering a particular technique called RNA silencing that adjusts the genomic underpinnings of the disease to restore normal function.

"Only I didn't really know anything about RNA silencing," said Ashley. "But I knew of someone who did." That someone was Andrew Fire, PhD, professor of genetics and of pathology, who had just won the Nobel Prize for discovering the biological mechanism Ashley wanted to co-opt.

"So I sent him a message out of the blue, saying 'Dear Professor Fire, you don't know me, but I'm a new assistant professor here at Stanford and I wonder if there's any chance I could pick your brain about an idea I have.'"

Not five minutes later, Ashley's phone rang.

"At that time I was so new, 90% of my calls were wrong numbers. So, when I answered, and the other person said, 'Hi it's Andy,' I racked my brain -- I didn't know any Andys."

Of course it then clicked that it was Andrew Fire on the line, and after some discussion with the Nobelist, Ashley began a years-long research project to develop a new gene therapy remedy for cardiomyopathy.

Twelve years later, the first paper from that effort has published online in Circulation, detailing a successful approach to treating a type of cardiomyopathy in mice through gene therapy. Ashley, now professor of medicine, of genetics and of biomedical data science, and Matthew Wheeler, MD, assistant professor of medicine, are senior authors. Kathia Zaleta-Rivera, PhD, a former postdoctoral scholar at Stanford, is the first author.

The new study is among the first to show how gene therapy could successfully treat restrictive cardiomyopathy, a condition that causes the walls of the heart to stiffen, inhibiting the muscle's ability to pump blood. Ashley's work, which he performed in cells and in mice, demonstrates the safety and efficacy of the approach, a necessary step in preparing the therapy for potential clinical trials.

Many different genes can underpin restrictive cardiomyopathy. Ashley's study focused on a particular type of restrictive cardiomyopathy caused by a mutation in a gene that supports muscle contractility, MYL2. Although the mutation is harmful to the gene's function it's not entirely detrimental. (Like humans, mice have two copies of any given gene.) In individuals with restrictive cardiomyopathy, only one copy of MYL2 is mutated -- the other functions just fine.

"The fact that at least one of the MYL2 gene copies is producing a normal protein gave us a thought," said Ashley. "We wondered if we could essentially 'turn down' the volume of the signal sent by the mutant gene copy." Then, with the faulty copy muted, the healthy copy could carry out the gene's proper function.

With the vision in mind, Ashley set out to test his RNA silencing approach in cells and in mice that carry the human gene involved in restrictive cardiomyopathy.

By way of a virus stripped of its normal viral contents, the scientists delivered to the mice a molecular package containing two key components: a molecule that would trigger the cells to slice up the bad copy of MYL2, and a string of DNA that help guide the slicing molecule to the appropriate place on the gene.

After successful delivery of the silencing agent, the scientists saw a range of changes -- from molecular to physical -- occur. Most importantly, they saw that the mice who received treatment lived longer. Those that were ill and untreated started dying around 50 days, whereas treated mice lived much longer. What's more, tissue analysis showed that the treated mice had lower levels of biomarkers that flag restrictive cardiomyopathy.

With the mutated copy of the gene subdued, the healthy dominant copy could take over, helping to decrease the overall stiffness of the heart and allow the muscle to contract, and therefore pump blood, better.

"We measure something called fibrosis, which is about as close as we can get to measuring heart stiffness," said Ashley. "And in those mice that were treated, we saw about a 25% drop in fibrosis."

With an overall successful run in mice, Ashley's next step is setting up clinical trials for the RNA-silencing treatment. In doing so, he and his lab have now tested the tactic in human cells -- blood cells taken from patients with cardiomyopathy. Through a series of experimental steps, the patient blood cells were coaxed into heart cells. Then, with a sort of mini, beating "heart in a dish," Ashley's team showed that they could improve how these cells contract using the RNA-silencing therapy.

"Right now there aren't any fully approved gene therapies for restrictive cardiomyopathy," said Ashley. "And we think this technique holds some real potential, so human trials are our next step."

Photo by Drew Patrick Miller

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