06 March 2023

A potential strategy to treat a rare bone marrow failure syndrome has been reported by researchers in the USA.

Research led by Washington University School of Medicine in St. Louis, USA, says the strategy for poikiloderma with neutropenia could also have implications for treating other bone marrow failure syndromes with similar underlying dysfunctions.

Although it was known that poikiloderma with neutropenia is caused by mutations in a gene called USB1, the precise mechanism of how the mutation causes bone marrow failure was unknown.

Writing in the journal Science, the team says they have identified a novel role for an enzyme, opening the door to future clinical trials.

Studying human embryonic stem cells engineered to model this syndrome, the researchers found a problem with the processing of microRNAs, which causes specific microRNA molecules to break down faster than they should. Without sufficient levels of these microRNAs, the stem cells can’t develop into normal blood cells.

First author Hochang Jeong said: “Our study shows that normal USB1 is cutting off the long tails of these microRNAs, which stabilises their structure, giving them time to do their jobs forming blood products.

“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.”

Although there is not yet a known way to restore the ability to properly remove the tails, investigational drugs already exist that block the enzymes responsible for putting the tails on. Blocking these enzymes – PAPD5 and PAPD7 – in poikiloderma with neutropenia could restore the equilibrium between the adding and subtracting of tails.

Co-senior author Luis Batista, associate professor of medicine, said: “We are working with different companies to develop better and more specific PAPD5 inhibitors to treat this rare syndrome.

“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.”


Jeong HC, Shukla S, Fok WC, Huynh TN, Batista LFZ, Parker R. (2023) “USB1 is a miRNA deadenylase that regulates hematopoietic development.” Science, doi: 10.1126/science.abj8379

Link: https://www.science.org/doi/10.1126/science.abj8379

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