Dr. Graham Erwin receives NIH New Innovator Award

Dr. Graham Erwin, assistant professor of molecular and human genetics at Baylor College of Medicine, has been awarded the National Institutes of Health Director’s New Innovator Award. This highly competitive award allows exceptional early career scientists to pursue bold, high-risk research approaches that traditional funding mechanisms typically cannot support. Erwin will receive $2.4 million for his work to create a new class of small molecules to edit the human genome and correct pathogenic mutations.

Erwin’s research focuses on the functional role of repetitive DNA in regulating gene expression. In a paper published in Science in 2017, Erwin and colleagues designed and synthesized a small molecule tool, synthetic transcription elongation factors (Syn-TEFs), to target a specific DNA repeat that silences frataxin expression in Friedreich ataxia, a severe neurodegenerative disease with no effective therapy. In cell and animal models, they showed that this tool could specifically bind to the DNA at the pathogenic repeat and then effectively recruit other proteins to facilitate normal production of frataxin, restoring the expression of the impacted gene. An analog of that molecule is now in Phase 1 clinical trials for patients with Friedreich ataxia. 

His new work will build on the previous study. Now, his team will work to synthesize and test a molecule that can bind to DNA and contract the repeat expression back to a normal length. Erwin compares the technique to molecular scissors.

“In our previous work, if the molecule is successful, patients would have to take the drug for life to maintain protein expression and halt progression of disease,” Erwin said. “Our goal with this work is to permanently correct the mutation and restore protein expression forever.”

Other gene-editing techniques such as CRISPR-Cas9 also permanently edit DNA mutations. But Erwin’s small-molecule technique will address a complication in those methods. Because CRISPR-Cas9 is so large, it requires a large delivery vehicle, a viral vector, to get into the cell. In some cases, these viral vectors can cause severe immune reactions in patients.

“Our small, organic molecules don’t require a delivery vehicle. These molecules can transiently get into the cell,” Erwin said. “Small molecules have been well-studied and are significantly less likely to trigger serious immune responses. They also often penetrate tissue more easily than larger vectors.” 
Once again, Erwin will focus his work on cell models of Friedreich ataxia, but if the technique is successful, it could be used to treat other diseases as well. Sixty human diseases are known to be caused by abnormal repetitive DNA sequences.

“These small molecules are rationally designed, so they can be programmed to target another repetitive DNA sequence in a different disease,” Erwin said.

The award, a part of the NIH Common Fund’s High-Risk, High-Reward Research program, supports unusually innovative research from early career investigators. Erwin’s research is funded by NIH grant (DP2HD121549). Read more about the High-Risk, High-Reward program here.