Researchers at Washington University School of Medicine in St. Louis say they have discovered a potential treatment strategy for a rare bone marrow failure syndrome named poikiloderma with neutropenia. The research may also have implications for treating other bone marrow failure syndromes with similar underlying dysfunctions.

The findings are published in Science in a paper titled, “USB1 is a miRNA deadenylase that regulates hematopoietic development.”

Poikiloderma with neutropenia is caused by mutations in a gene called USB1, however, the specifics of what the mutations do to cause bone marrow failure are not fully understood.

“There are no cures for poikiloderma with neutropenia,” explained co-senior author Luis Batista, PhD, an associate professor of medicine. “Patients are at high risk of dying from complications of infections, and scientists had no idea why mutations in this gene lead to bone marrow failure. In this new study, we found a novel role for an enzyme that opens the door to future clinical trials. There are investigational drugs that block this enzyme, so we are hopeful that clinicians who treat these patients may find this a promising strategy to pursue.”

A new study from researchers at  Washington University School of Medicine in St. Louis identifies a possible treatment strategy for some bone marrow failure syndromes. Shown are human embryonic stem cells engineered to have a mutation that causes poikiloderma with neutropenia, a bone marrow failure syndrome that increases a patient’s risk of developing dangerous infections. [BATISTA LAB]
Studying human embryonic stem cells engineered to model this syndrome, the researchers, including co-senior author Roy Parker, PhD, of the University of Colorado, Boulder, found a problem with the processing of microRNA, which causes specific microRNA molecules to break down faster than they should.

“Our study shows that normal USB1 is cutting off the long tails of these microRNAs, which stabilizes their structure, giving them time to do their jobs forming blood products,” said first author Hochang Jeong, PhD, a postdoctoral research associate in Batista’s lab.

“When USB1 is mutated in this disease, these microRNA tails are much longer than they should be. We know that having longer tails makes microRNAs and other classes of RNA molecules more easily targeted for degradation. What we learned is there should be an equilibrium between the enzyme that puts the tails on and the enzyme that chops off the tails.”

There is not yet a known way to restore the ability to properly remove the tails. However, there are investigational drugs that block the enzymes responsible for putting the tails on. Blocking this enzyme in this disease potentially could restore the equilibrium between the adding and subtracting of tails.

The enzymes responsible for adding the tails are called PAPD5 and PAPD7, and inhibitors of these enzymes have been investigated in human clinical trials for other diseases, including hepatitis B. For this study, the researchers used a PAPD5 inhibitor called RG7834 and are now working with industry partners to develop new PAPD5 and PAPD7 inhibitors.

“We are working with different companies to develop better and more specific PAPD5 inhibitors to treat this rare syndrome,” Batista said. “In my lab, we are big advocates for the study of rare diseases. Combined, rare diseases are not rare at all, and these patients deserve our attention. PAPD5 inhibition is poised to be a potential treatment for other bone marrow failure syndromes.”

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