Drug once tested for hep b could help rare bone marrow syndrome

Drug once tested for hep b could help rare bone marrow syndrome

Scientists have known the genetic mutation behind the rare bone marrow syndrome poikiloderma with neutropenia (PN) for some time, but exactly how the mutation causes the condition has remained a mystery. Now, researchers think they’ve cracked the case—and found a potential treatment, too.

In a study published March 3 in Science, a team from Washington University described how they identified a pathway between a loss of function mutation in the USB1 gene and the inability of bone marrow to make sufficient blood cells, or bone marrow failure. The researchers also showed that a drug that had previously been studied in clinical trials could reverse the deficits by blocking a key enzyme. They are now working with industry partners to develop new treatments.

“In this new study, we found a novel role for an enzyme that opens the door to future clinical trials,” co-senior author Luis Batista, Ph.D., said in a press release. “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.”

PN was first described back in 1991, when New Mexico physician Carol Clericuzio, M.D., and colleagues identified a rare syndrome among Indigenous Navajo children who had a raised, red rash on their arms and legs that spread in a circular pattern before giving way to pigmentation changes and visible dilated blood vessels on the surface of the skin. Besides the rash, patients also suffered from a dangerous lack of white blood cells called neutrophils, leaving them prone to deadly infections and a greater risk of skin and blood cancer.

Researchers later found PN in patients from other backgrounds and established a connection between the disease and the USB1 mutation. But despite knowing the culprit gene, they still didn’t know enough about how USB1 caused bone marrow failure to establish a mechanism.

To see if they could find one, the Washington University researchers used CRISPR-Cas9 to create the PN gene mutation in human embryonic stem cells. Finding that the stem cells with the mutation looked and acted normal, they stimulated them to transition into blood cell precursors called hematopoietic progenitor cells.

Initially, cells from both the mutated cells and the control line differentiated as expected. But 16 days after starting the experiment, the team noticed that progenitor formation in the mutated cells had dropped off. A series of cell and RNA sequencing studies revealed why: A key microRNA molecule required for blood cell differentiation was being destroyed more quickly than it should, preventing the cells’ formation.

Under normal conditions, an enzyme regulated by USB1 stabilizes a type of molecule called microRNA by removing its “tail,” a series of nucleotides that signal that the microRNA should be destroyed. That gives the microRNA time to “do its job,” as study first author Hochang Jeong, Ph.D., said in the press release. Then, when the microRNA is done, the enzymes PAPD5 or PAPD7 put the tail back on.

But without the “tail off” enzyme, the microRNA is destroyed before it can help the progenitor cells differentiate into blood cells. That leads to bone marrow failure and the complications that come with it.

To see if they could rebalance the enzymes and rescue the microRNA from destruction, the scientists turned to the PAPD5 inhibitor RG7834 (alternatively known as RO7020322). The drug had once been assessed in clinical trials by Roche for hepatitis B, but the company scrapped its development.

The researchers treated UB1 mutated cells with RG7834 and studied how it affected the placement of tails on the microRNA. After seeing that the drug increased the amount of tail-free microRNA in the cells, they assessed whether it could also restore blood cell differentiation. Indeed, it did. Treatment with RG7834 resulted in improved neutrophil formation in the mutant cells, suggesting it could be a potential treatment strategy for PN. A final round of experiments where the researchers directly expressed microRNA levels in cells with the USB1 mutation showed that this too restored blood cell formation, further validating their findings.

The researchers are now working with undisclosed industry partners to take their findings to the next stage. They hope that their findings will lead to new treatments not only for PN but potentially for other bone marrow syndromes that work through similar mechanisms.

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