RARE Daily

UCSD and Ionis Use ASO to Target Multiple Myeloma

January 20, 2021

Rare Daily Staff

Researchers at the University of California, San Diego and Ionis Pharmaceuticals report that targeting a gene that allows myeloma stem cells and tumor cells to proliferate and survive, could treat the blood cancer.

Many patients with multiple myeloma develop resistance to treatments in part because cancer stem cells drive the disease. Cancer stem cells are cells that continually self-renew. If a therapy doesn’t destroy these malignant stem cells, the cancer is likely to keep coming back.

The researchers sought to silence the IRF4 gene in mice with an antisense oligonucleotide, an engineered piece of DNA designed to bind to the genetic material coding for IRF4 and causing it to degrade. Past studies have shown that high IRF4 levels are associated with lower overall survival rates for patients with the disease.

In a study published January 20, 2021 in Cell Stem Cell, the scientists detail their successes inhibiting IRF4. The oligonucleotide—an investigational antisense medicine developed by Ionis and known as ION251—lowered disease burden, reduced myeloma stem cell abundance and increased survival of mice bearing human myeloma, according to preclinical study data.

The authors of the study say the results support a phase 1 clinical trial recently launched to assess the safety and efficacy of the treatment, known as ION251, to treat humans with myeloma.

One challenge myeloma researchers face is that myeloma cells don’t grow well in laboratory dishes. To study the disease and test new treatments, the researchers transplant human myeloma cells into mice that lack an immune system and thus won’t reject the human cells—making avatars of each unique patient, in a way.

The team tested ION251 on these myeloma mouse avatars. Compared to untreated mice, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. What’s more, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did. There were 10 mice in each treatment or control group, and they received daily doses of ION251 or a control for one week, followed by three doses per week.

In separate experiments using human cells isolated from myeloma or healthy donor samples, the doses of ION251 used were enough to eradicate the myeloma stem cells while sparing healthy blood cells.

“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank—in the treated mice, we couldn’t find any myeloma cells left for us to study,” said co-senior author Leslie Crews, assistant professor in the Division of Regenerative Medicine at UC San Diego School of Medicine. “It makes the science more difficult, but it gives me hope for patients.”

Photo: Leslie Crews, assistant professor in the Division of Regenerative Medicine at UC San Diego School of Medicine

Stay Connected

Sign up for updates straight to your inbox.