Transcriptional therapy comes of age

Designing drugs to control gene transcription “is where careers go to die,” Aseem Ansari was told as a postdoc. This essential cellular process, which deciphers information stored in the genome, causes various diseases when it goes wrong. But trying to control the proteins involved in copying genes into RNA, as the first step in gene expression, looked technically too difficult in the mid-1990s to be of any therapeutic use.

The field has advanced significantly since then. And Ansari, now the chair of the chemical biology and therapeutics department at St. Jude Children’s Research Hospital in Tennessee, is leading the charge to develop drugs that control transcription as a way to treat disease.

That’s important because a range of hard-to-treat disorders, including pediatric cancers, are driven by defects in transcription and associated disruption of the finely balanced gene networks that govern cell functions. In theory, molecules that can rebalance these faulty cellular processes could offer a whole new suite of treatments.

“It's just the beginning of a very exciting new era,” Ansari says.

Targeting transcription factors

One of the conditions that could benefit from transcriptional therapy is a genetic disorder called Friedreich’s ataxia. It affects one in 40,000 people, most commonly those of European descent. The disorder is caused by an erroneous long chain of repeating DNA bases in the FXN gene, which prevents the cell’s transcriptional machinery from reading the entire gene and producing the correct protein. From childhood, the nerves that control actions such as walking, speech and balance begin to degenerate.

There is no cure for Friedreich’s ataxia, but Ansari has developed a chimeric small molecule that uses one half to find and bind the disease-causing sections in the FXN gene, while using the other half to pull in proteins that allow transcription to proceed normally. This proprietary small-molecule compound – also known as a GeneTAC – has shown benefits in animals and is looking “very promising,” says Ansari, who cofounded a company called Design Therapeutics that is commercializing geneTACs to treat Friedreich’s ataxia and other diseases caused by malfunctioning transcription.

“What we’ve done is convert a molecule that was of academic interest into something that might have therapeutic potential,” he says. “Our Lego-block-like design allows us to tack different small molecules together to control gene transcription in different ways. It is the beginning of a whole new class of GeneTAC molecules.”

A geneTAC is a synthetic version of a transcription factor, one of the many proteins involved in gene expression inside the cell. Transcription factors bind to specific sites on DNA and control transcription. When Ansari began decades ago, it seemed almost impossible to precisely target a particular transcription factor with a drug-like molecule.

The exception is a class of transcription factors, called nuclear receptors, which are among the top five drug development targets producing multibillion-dollar drugs. These receptors naturally bind the hormones oestrogen and testosterone, so their hormone binding pockets also stick to analogues of those hormones and small drug-like molecules. Such molecules have been used to target nuclear receptors that drive breast and prostate cancers, respectively.

The vast majority of other transcription factors are thought to lack such druggable pockets. Ansari describes the molecular interactions between these factors and the gene transcription machinery as “fuzzy”, “weak”, and “impossibly slippery”, making them among the toughest challenges for drug development.

Still, with 700 such transcription factors in the human body, this represents an enormous opportunity against diseases that are currently untreatable.

A long road

Rather than targeting the natural transcription factors in the cell with a drug, Ansari saw a way to replace them and gain control over which genes would be active or silent. In 1998, he started his research with Anna Mapp, then a postdoctoral fellow with chemist Peter Dervan at Caltech, and showed that attaching simple peptides to DNA-targeting molecules created synthetic transcription factors. These hybrid molecules were a hundred times more efficient at targeting the gene than a natural transcription factor in cell-free systems. “I thought we were going to change the world,” Ansari says. The problem was that it wouldn’t work inside living cells or animals.

Using a psoriasis drug, Ansari next created chemical cross-links between the DNA and the synthetic transcription factor. This revealed that the molecule was not binding the DNA where he expected, but instead to genomic locations with long chains of repeats of the same DNA code.

These results explained the difficulties. He suspects that some component of the cellular machinery is “cleaning” the DNA, removing the molecules that are bound. So even if the synthetic transcription factor reaches its intended sequence in the target gene, it is quickly knocked off.

With long portions of repeating code, however, the molecule can easily find another nearby stretch to bind when it is knocked off— a form of molecular whack-a-mole. This presented a powerful new tool for treating neuromuscular and developmental diseases caused by extended DNA repeats, such as Friedreich’s ataxia.

Diverse approaches

When Ansari joined St. Jude in 2019, he met chromatin biologist Charles Roberts, who directs the St. Jude Comprehensive Cancer Center, and teamed up to create a gene-regulation interest group. They expected only 15 faculty members to participate, but the group quickly grew to more than 70. This gathering of researchers grew into an annual symposium on transcription therapy that covers different aspects of transcription and attracts researchers worldwide.

“There’s a huge growth in interest in the area,” says Anna Mapp, now a chemical biologist and associate dean at the University of Michigan. At last year’s symposium, Mapp presented her research on how transcription factors recognise their binding partners. “It brings people from many different perspectives,” she says. “We’re not all usually at the same scientific meetings, and St. Jude’s transcription therapy symposium really brings everybody together.”

Jay Bradner, president of the Novartis Institutes for Biomedical Research and a speaker at the 2021 symposium, agrees. “Few conferences exist with this focus, and consequently the gathering was very engaging,” he says.

Researchers in the field are taking diverse approaches to find ways to regulate transcription, including controlling access to the DNA itself.

Most of the DNA in our cells is tightly packaged with proteins in a complex called chromatin. “Chromatin is a key gatekeeper,” says Ansari. “At the end of the day, the transcription factor has to access the genome. If that does not occur, then none of the other steps are possible.”

One of the speakers at this year’s symposium, Cigall Kadoch, a pediatric oncologist at the Dana-Farber Cancer Institute, presented research on how the cell targets certain stretches of DNA to make them accessible to transcription. It does this through specific markers that direct so-called chromatin remodelling complexes.

The power these remodeller markers have over transcription make them an appealing target for drug development, and Kadoch’s spinoff company now has candidate molecules in phase one clinical trials for acute myeloid leukaemia and synovial sarcoma.

“It’s been very rewarding to see this area of biology proceeding, after it was once deemed impossible to go after,” she says.