First came gene therapy. Now: transcription therapy

Aseem Ansari of St. Jude Children’s Research Hospital shared 10 years of research on transcription therapy at the ScienceWriters2022 conference. (Photo by Angel Kumari.)

Twenty years ago, when Aseem Ansari became engrossed in transcription therapy—using synthetic molecules to counteract the result of a malfunctioning gene circuit—he was met with cold skepticism. Ansari’s well-wishers warned him that pursuing transcription therapy would be “career suicide.” Ansari ignored the skeptics, and today he leads a team at St. Jude Children’s Research Hospital working to design unimaginable therapies.

The once unthinkable and undoable is now achievable, says Ansari, who holds the R. J. Ulrich Endowed Chair and chairs the Department of Chemical Biology and Therapeutics at St. Jude. He has also co-founded a company, Design Therapeutics, which plans to utilize GeneTACS, synthetic transcription factors, for treatment of rare diseases.

Ansari presented a decade’s worth of research on Oct. 23 during the New Horizons in Science briefings organized by the Council for the Advancement of Science Writers, part of the ScienceWriters2022 conference in Memphis, Tenn.

Ansari and his team have discovered a possible treatment for Friedreich’s ataxia, an inherited neurodegenerative movement disorder. His team is patiently waiting for the results of clinical trials performed in March 2022. Based on the success rate of phase one, two, and three trials alongside long-term chronic treatment, Ansari predicts that transcription therapy could help patients with Friedreich’s ataxia. This therapeutic design could potentially be applied to other incurable diseases.

Friedreich’s ataxia is caused by faulty expression of the FXN gene, which codes for the protein frataxin, essential for cell survival and energy production. Affected patients have an astronomically high number of repeats of a certain sequence in their FXN genes. As a result, the cell’s machinery is unable to read the gene and produce frataxin. The low production results in neuromuscular dysfunction that impairs patient movement.

Using transcription factors to control gene expression

Transcription is the first step in the process by which cells translate coded DNA sequences to produce proteins for use in the body. Transcription factors regulate gene expression by binding to the DNA at a specific site and activating gene transcription. In other words, transcription factors are like light switches that turn gene expression “on.” In Friedreich’s ataxia, GeneTACS are used to counteract low expression of FXN by binding to the gene and employing transcription production proteins to increase transcription.

“We’re targeting transcription factors. We are targeting genomic lesions. We are trying to overcome in an informed way the mechanistic properties that are causing the disease,” Ansari explained to the science writers. A genomic lesion is damage to a segment of DNA that alters the function of the gene.

Unlike gene therapy, where parts of a faulty gene are either replaced or deleted, transcription-based therapeutics rely on synthetic transcription factors to increase or decrease gene expression. These synthetic transcription factors replace malfunctioning transcription factors since targeting malfunctioning transcription factors is still a major challenge in the field. This therapy’s design relies on the principles of the natural system of transcription.

“What I’m hinting here is that working with natural systems, you might be able to address the problem of targeting transcription factors,” said Ansari.

Despite what the skeptics once said, Ansari sees the challenge as “eminently doable, logically addressable, and potentially game-changing” in attacking the many hard-to-treat disorders where problems with DNA transcription play a role.

The challenge is significant, and so is Ansari’s determination.

“We’ve been trying to build up momentum for taking this problem seriously,” he said. “We have been thinking about it as creatively as possible and not limiting ourselves to St. Jude Children’s Hospital alone, but also collaborations with scientists at the cutting edge of the field elsewhere to engage and enhance the ability to take on the impossible.”

Angel Kumari (she/her) is a freelance science writer and master’s student in the Johns Hopkins University science writing program. She is a Clemson University graduate with a degree in biological sciences and minors in English and microbiology. Kumari received a New Horizons travel fellowship to attend ScienceWriters2022. Follow her on Twitter @akumsss or visit her website