RNA Institute awarded $2.5M to advance ‘RNA Rescue’ in fight against myotonic dystrophy

Courtesy of the University at Albany

University at Albany scientists have been awarded $2.5 million to advance research aimed at finding a cure for myotonic dystrophy — the most common form of adult-onset muscular dystrophy, impacting about 1 in 2,100 New Yorkers. 

The announcement comes as UAlbany prepares to mark International Myotonic Dystrophy Awareness Day on Thursday, commemorated in the Capital Region with green lights displayed on campus and  the major government buildings in Albany.  Myotonic dystrophy (abbreviated DM) affects muscle tissue, but also the heart, eyes and brain. Symptoms include myotonia (an inability to relax muscles), muscle wasting and muscle weakness. Patients can also experience lethargy, cataracts and glucose intolerance. Vision, speech, digestion and cognitive function are often impaired. The disease can affect people at any life stage, starting at birth.

“The symptoms of myotonic dystrophy are extremely varied — in terms of body systems affected, age of disease onset and symptom severity,” says Andrew Berglund, director of the College of Arts and Science’s RNA Institute and a co-principal investigator on the grant. “This complexity makes diagnosis challenging. And while myotonic dystrophy is familiar within the neurological community, it is largely unknown among general practitioners. This is why it often takes up to 8-10 years to reach a DM diagnosis; many doctors simply do not recognize the signs.”

Berglund has partnered with interdisciplinary researchers from across the country and the world to advance myotonic dystrophy research centered at UAlbany. He and his colleagues at the RNA Institute are developing new drugs to target myotonic dystrophy at the molecular level. “DM patients are prescribed drugs to treat individual symptoms — some take dozens every day — but these drugs do not address the genetic root of the problem. Our team is working to target the disease itself, not the symptoms. Our previous work has revealed compounds that show great promise, and this grant will allow us to continue creating and testing new compounds.”

How DM takes hold

Myotonic dystrophy is caused by “repeat expansion” — a type of genetic mutation that is also responsible for diseases like Huntington Disease and ALS.

A “repeat” is when a small section of the genetic code occurs multiple times in a row in our DNA. Repeats are common in our genome, but typically occur no more than 20-30 times in one region and don’t frequently change size. In people affected by a repeat expansion disease, this repetition grows and expands — up to tens of thousands of times at the same region of the genome — disrupting important processes in the cell. Where this repetition happens within the genome determines what disease occurs and how symptoms are expressed.

Ribonucleic acid (RNA) is a molecule in cells that transmits information from DNA to ribosomes to produce proteins.

“When repeat expansions are made into RNA, we get what is called toxic RNA,” explains John Douglas Cleary, a co-principal investigator on the grant and a collaborative staff scientist at the RNA Institute. “This toxic RNA pulls in proteins from within the cell, like a magnet dropped into a pile of metal filings. When these proteins are stuck to the toxic RNA, they can’t do their normal jobs to support critical functions throughout the body. This is how the disease affects so many systems.”

Unlike other mutations, repeat expansions happen at different rates in different parts of the body. This is why symptoms and severity are so wide-ranging.

And, because the repeat expansion grows — both within individuals throughout life, and as it is passed through generations ­— symptoms increase in severity, with earlier age of onset, from one generation to the next. This is called genetic anticipation.

Kaalak Reddy, a co-principal investigator on the grant, is a scientist working in the RNA Institute. “Genetic anticipation contributes to underdiagnosis,” Reddy explains. “For example, within a family, a grandparent with myotonic dystrophy may only experience mild symptoms, such as cataracts. But then, several generations later, the disease is identified when a mother with DM gives birth to a baby with severe symptoms like hypotonia (low muscle tone) and is unable to move its limbs.”

Searching for a cure

The RNA Institute team’s focus is on “small molecules” — compounds small enough to directly enter cells and target specific processes happening within them. The team is synthesizing novel compounds designed to target toxic RNA and reduce the effects of repeat expansion — a process called RNA rescue. The team’s ultimate goal is to develop a drug that can be delivered through an oral tablet and reach all organs in the body including the heart, muscles and brain.

Berglund explains, “Myotonic dystrophy is systemic, so while certain areas of the body may be more affected than others at different points in time, the disease is everywhere. If we can make a drug that stops or reduces the toxic RNA, this will address the problem throughout the body. Instead of treating one symptom at a time, this approach hopefully would address all symptoms everywhere.”

The research pipeline begins in the digital world. RNA Institute research scientist and advanced computational facility manager Sweta Vangaveti creates computer models of new chemical compounds and tests them against the toxic RNA using a simulation. Compounds that prove effective are synthesized by Hormoz Mazdiyasni, a medical chemist in the Berglund lab.

The Berglund and Reddy labs then test these compounds using their own custom-made myotonic dystrophy cell line. This first step involves fast growing HeLa cells, of the famous line of cancer cells derived from patient Henrietta Lacks, that express the toxic RNA of myotonic dystrophy and can be grown and ready for testing in 3-4 days.

How well a compound might behave as a drug is determined by measuring relative levels of toxic versus healthy RNA in each sample after the compound has been added.

Compounds that are successful at reducing toxic RNA without harming healthy RNA are tested in skin and muscle cells generously donated by people affected by DM and grown in the RNA Institute labs. Those compounds that do well with muscle cells are administered to mice. At this stage, the research team can assess effects of the compounds on symptoms that more closely match what happens in patients, like myotonia.

So far, they have tested thousands of compounds via computer simulation and cell line testing. About a dozen have made it to mouse trials.

“Each stage of testing gets us closer to a clinical trial in human patients,” Cleary explains. “At every stage, we also pay keen attention to safety and toxicity. If a compound shows sign of an off-target effect, we go back to our computational scientists and medicinal chemists to determine why this might be happening and what needs to be changed to fix the problem.

“This intensive iteration is critical to ensure that only compounds that are safe and effective are advancing to mice, and then eventually onto people. The process is extremely time and resource intensive — and is why funding, like this new grant from NIH, is so critically needed.”

Visions for the future

“The myotonic dystrophy research community is small but tremendously dedicated,” Berglund says. “In fact, many of the people working on the disease have personal connections to the research, including friends and family members affected by DM.

At the RNA Institute, scientists are working to create a hub of research, training and education to raise awareness of DM, help medical practitioners better detect symptoms, and advance research towards treatments.

“Our vision is to continue to grow our capacity, both in infrastructure and people, and establish the New York Myotonic Dystrophy Center to further solidify and coalesce efforts to fight this disease.”

With this latest funding from NIH’s National Institute of Neurological Disorders and Stroke, plus generous support from the Canada-based Marigold Foundation — which has given $865,000 to support the creation of a myotonic dystrophy center at UAlbany — and $1 million in federal funding secured by Congressman Paul Tonko earlier this year, the team is well on its way.

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