Designer molecule points to treatment for diseases caused by DNA repeats

Photo of Aseem Ansari
Professor Aseem Ansari.

Professor Aseem Ansari’s research group in the Department of Biochemistry has designed a molecule that can precisely target a specific part of DNA and “switch on” genes located there. Specifically, their molecule targets short sequences of DNA that repeat many times (GAA1-GAA2-GAA3-…). These GAA repeats cause the rare but fatal disease Friedreich’s ataxia, and molecules that target such sequences would open doors for possible treatments of the disease and many others like it caused by other repeats.

Through more than a decade of research, Ansari’s group tested many different synthetic genome readers, how they bound to DNA, and what changes would make binding to target DNA sequences more precise. They’ve harnessed a molecule that has the needed chemical complementarity to bind to the GAA repeats present in the genome of individuals who have Friedreich’s ataxia and then bring cellular machines to help the genome function properly. They’ve reported these results in the journal Science online on Nov. 30, 2017 but in print today (Dec. 22, 2017) in the journal’s 2017 “breakthrough” issue.

“We asked ‘could you control genome function by making drug-like synthetic molecules that go to specific places in the genome?’ ” Ansari explains. “You can think of the molecule traveling along the genome and reading it like braille, feeling the edges of the DNA to see if it can read the correct section it will latch onto. Once it locates its genomic zip code, the second half of the molecule functions like a homing beacon to precisely target the cell’s heavy machinery to fix the roadblock at that site and nowhere else.”

Aseem Ansari's group talks about research in the lab.
Aseem Ansari (center), professor of biochemistry, talks with his research group about their findings in his lab in the DeLuca Biochemistry Laboratories on the UW–Madison campus. Photo: Bryce Richter.

In the Ansari Lab, Graham Erwin, Matthew Grieshop, and Asfa Ali worked to design this prototype molecule with other UW–Madison collaborators, colleagues across the globe at premiere biomedical institutions in India, Harvard Medical School, and the pharmaceutical company Novartis.

Friedreich’s ataxia is a rare but fatal disease with no known cure caused by repeats of GAA nucleotides near the gene coding for the protein frataxin, which mitochondria — the cell’s power supplier — need to process the body’s energy. These repeats — that can number in the thousands — cause the DNA to wind up and become unavailable to the cellular machinery that’s ultimately responsible for making frataxin.

The lack of the protein causes developmental impairment as early as age five, particularly in places like the heart and brain that use a lot of energy. These repeats are passed on genetically and so can build over generations. Even though one American in 110 is a carrier, the severity of the disease is such that it only appears in approximately one in 50,000.

“We were very surprised in our earlier research to find that our synthetic genome readers can actually access the wound-up parts of DNA that everyone thought were off limits,” says Ansari, who is also with the Genome Center of Wisconsin at UW–Madison. “We are now able to precisely tailor molecules to get into this hostile genomic terrain and ‘turn on’ those parts of DNA that were inaccessible.”

The Science paper is the culmination of nearly 15 years of research in this area. After a decade of studying binding to millions of different sequences Ansari and other researchers couldn’t get their molecules to bind where they needed. Just as they were running low on morale and funds, they decided to ask the genome for advice.

Hamilton family photo.
Three years ago, Annie Hamilton (center) was diagnosed with Friedreich’s ataxia. Tom and Karen, her parents, have formed a foundation to support research aimed at curing FA and other rare diseases. “We are very hopeful, very optimistic,” says Tom. Courtesy of Cure FA Foundation.

While very precise, the molecule does bind to other parts of the DNA that also have GAA sequences. However, Ansari says the molecule causes little “collateral damage” in these areas in the animals and patient cells they tested in the lab. This is because none of the other areas are awaiting the cellular machinery like the blocked frataxin gene in patients.

“Out of three billion options across our genome, this designer molecule stops at roughly 250 places — so we’ve basically narrowed the search space down by about 10,000-fold,” Ansari explains. “Of those 250, only one is ready to receive the signal delivered by our precision-tailored molecule.”

The lab’s future work in this area will follow many avenues. Ansari says this approach can become even more precise. While the repeats make it difficult for the cell to make the necessary protein, some of it is still made, enough to keep the individual going but with ever increasing developmental and neurological problems. The amount of frataxin made — and hence severity of the disease — corresponds with the number of repeats. Ansari says his team is going to continue to make their molecule more precise where an individual with fewer repeats gets a different version than another with more, for example.

Ultimately their next step is ensuring their molecule is not toxic to mice. Toxicity to mice would take the lab back to the drawing board but if the promising prototype is safe they can also begin to analyze how the molecule distributes in mice. Ansari would like to see the molecule tested in real patients down the road once further tests show that it is safe and effective.

“In medicine today, we fix the symptoms, but what we want to fix is the underlying root of the disease,” Ansari says. “We want to correct problems that a person inherits via their genome, and along the way develop an exciting new approach to precision medicine.”