Dr. Graham Erwin, an assistant professor of molecular and human genetics at Baylor College of Medicine, has been honored with the prestigious National Institutes of Health (NIH) Director’s New Innovator Award. This accolade, which provides $2.4 million in funding, is designed to empower exceptional early-career scientists to explore high-risk, innovative research avenues that conventional funding sources typically overlook.
Erwin’s research will focus on developing a new class of small molecules aimed at editing the human genome to correct pathogenic mutations. His groundbreaking investigations delve into the functional roles of repetitive DNA in regulating gene expression, a significant factor in various genetic disorders.
In a pivotal paper published in Science in 2017, Erwin and his team created a small molecule tool known as synthetic transcription elongation factors (Syn-TEFs). This tool was designed to target a specific DNA repeat responsible for silencing frataxin expression in Friedreich ataxia, a debilitating neurodegenerative disease currently lacking effective treatments. Their research demonstrated that Syn-TEFs could precisely bind to the pathogenic DNA repeat, successfully recruiting proteins necessary for the normal production of frataxin. This approach has progressed to the point where an analog of this molecule is now undergoing Phase 1 clinical trials for patients afflicted with Friedreich ataxia.
Erwin’s latest project will build on this foundational work. His team intends to synthesize and test a new molecule capable of binding to DNA and reducing the expression of the harmful repeat to a normal length. Erwin likens this innovative 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 explained. “Our goal with this work is to permanently correct the mutation and restore protein expression forever.”
Comparative gene-editing techniques such as CRISPR-Cas9 are also designed to provide permanent edits to DNA mutations. However, Erwin’s approach using small molecules addresses a significant complication inherent in those methods. The CRISPR-Cas9 system is relatively large and necessitates a substantial delivery vehicle, often a viral vector, to transport it into human cells. In some instances, these viral vectors can provoke severe immune reactions in patients.
“Our small, organic molecules don’t require a delivery vehicle,” Erwin stated. “These molecules can transiently get into the cell. 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.”
While Erwin’s primary focus remains on cell models of Friedreich ataxia, the implications of his work could extend to a broader range of diseases. Currently, over sixty human diseases are linked to 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 added, highlighting the potential versatility of his research.
With the support of the NIH New Innovator Award, Erwin is poised to make significant strides in gene editing, potentially revolutionizing treatment options for various genetic disorders.
