Part III: The Power and Promise of RNA
In 2000, Lynne Maquat came to the University of Rochester as professor of Biochemistry and Biophysics at the School of Medicine and Dentistry. In 2007, she founded the Center for RNA Biology: From Genome to Therapeutics.
Taking note of her research skills and long-term productivity, the NIH transitioned one of Maquat’s two existing R01’s to a MERIT Award, which secures funding for her research and training through 2023.
As she continues to peel back the layers of understanding with respect to RNA biology, her work clarifies that while nonsense-mediated mRNA decay (NMD) evolved to shield humans from innate mistakes, it has the power to cause harm, too.
Inherited and acquired mutations can also introduce premature termination codons. In fact, one-third of all genetic disorders are caused by mutations that result in a premature termination codon. Many individuals with beta0 thalassemia have a nonsense mutation that introduces a premature termination codon in the gene encoding the beta-globin protein. The premature termination codon springs the NMD machinery into action and the mRNA transcript for beta-globin protein is destroyed. No beta-globin protein is produced and patients can’t make hemoglobin.
Some individuals with cystic fibrosis are similar. A nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to a premature termination codon and NMD follows. The CFTR protein, which is responsible for regulating the flow of salt and fluids in and out of cells, is defective or isn’t made. The result is the buildup of thick mucus and persistent lung infections that characterize cystic fibrosis.
In both of these cases, if you could override or stop NMD—for example, by efficiently suppressing the nonsense codon—normal, healthy proteins would be made and individuals wouldn’t be sick.
Thanks to 35 years of research by Maquat and others, scientists are beginning to put the mechanistic findings related to NMD to use to design treatments. Maquat and her team are focusing on the many diseases that are dominantly inherited because NMD fails to occur, despite the presence of a premature termination codon.
“RNA presents an alternative universe of drug targets and gives us an opening to correct diseases that you can’t reach with conventional drugs,” says Charles Thornton, MD (Flw ’90, ’92), the Saunders Family Distinguished Professor in Neuromuscular Research, who is partnering with several groups to develop RNA-based therapies for myotonic dystrophy and ALS. “Much that’s being done in this area builds on Lynne’s work, and I count myself fortunate to be in the same institution, to benefit from her wisdom, and indirectly, from the supportive, collegial environment she helps to create.”
"RNA presents an alternative universe of drug targets and gives us an opening to correct diseases that you can't reach with conventional drugs."
- Charles Thornton, M.D.
Therapies in development include small molecules inhibiting the core NMD machinery, and so-called “read-through” therapeutics that aim to turn early “stop” signals into “go” signals so that genetic instructions are read all the way through and full-length proteins are made. These treatments fit squarely into the domain of precision medicine, as they are based on the molecular underpinnings that lead to disease in the first place.
In the last several years, Maquat has discovered that NMD is a more dynamic pathway than originally thought. It also helps cells adjust to changes in their environment and more rapidly respond to certain stimuli.
For example, Maquat and Maximilian Popp, PhD, a research assistant professor in her lab, found that exposing breast cancer cells to a molecule that inhibits NMD prior to treatment with doxorubicin—a drug used to treat leukemia, breast, bone and other cancers—hastens cell death. They speculate that blocking NMD primes cells for programmed death by boosting the activity of genes that respond to the cellular stress caused by chemotherapy.
The study, published in Nature Communications in 2015, is one of several that describe a role for NMD beyond quality control, raising the possibility that drugs targeting NMD could prove useful in other situations. As new information regarding NMD continues to emerge, Maquat believes it could lead to additional technological and clinical advances not yet imagined.