YSM Issue 97.1
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FOCUS<br />
Immunology<br />
A NEW IMMUNE<br />
DRUG?<br />
HOW STRESS,<br />
WHITE BLOOD CELLS,<br />
AND IMMUNITY<br />
INTERSECT IN A485<br />
BY YOSSI MOFF<br />
ART BY CARA CHONG<br />
Our bodies are constantly under siege<br />
by dangerous pathogens. Thankfully,<br />
our biological systems have<br />
developed immune defenses to fight off these<br />
pathogens and stave off illness. White blood<br />
cells, which are produced by bone marrow, lie<br />
at the center of our immune system. Without<br />
them, we cannot fight off disease. For patients<br />
with bone marrow damage, however, this<br />
shield is compromised.<br />
Currently, there are a few ways to fight off<br />
disease in spite of injured bone marrow, such<br />
as antibiotics, immunoglobulin therapy, and<br />
drug treatments to stimulate white blood cell<br />
production. In many cases, though, these<br />
treatments fall short. Thanks to recent work<br />
by Nikolai Jaschke, a postdoctoral researcher<br />
in the Wang lab at Yale, that might change.<br />
Jaschke discovered new therapeutic potential<br />
in a synthetic molecule called A485, which<br />
was originally developed by a pharmaceutical<br />
company named AbbVie in 2017. He<br />
theorized that A485, which previously<br />
demonstrated potential anti-tumor effects,<br />
may have more effects than what its original<br />
characterization suggested—among them,<br />
a mechanism to combat infection in people<br />
with injured bone marrow.<br />
Putting A485 to the Test<br />
Produced by bone marrow, white blood<br />
cells enter the bloodstream and tissues, where<br />
they can rally against pathogens to protect<br />
from infection. If bone marrow is injured or<br />
experiences failure, it is unable to produce<br />
sufficient numbers of white blood cells. A<br />
severely low white blood cell count leads to an<br />
increased risk of infection and complication.<br />
Currently, patients who exhibit bone<br />
marrow failure are treated with granulocyte<br />
colony-stimulating factor (G-CSF). G-CSF is<br />
naturally produced by the body to stimulate<br />
the production of neutrophil granulocytes,<br />
the white blood cells that form the front line<br />
of defense against infection. G-CSF has also<br />
been developed into a drug administered<br />
to counteract a drop in white blood cells,<br />
known as neutropenia. However, some<br />
patients treated with G-CSF following bone<br />
marrow injury may still develop neutropenia<br />
and subsequent infection. This complication<br />
is known as acute neutropenic fever and is<br />
currently hard to tackle therapeutically.<br />
Enter Jaschke and his research on A485.<br />
Previously published research on A485 by<br />
AbbVie had shown that A485 could inhibit a<br />
histone acetyltransferase domain. Mutations<br />
in this domain are often associated with<br />
leukemia, a cancer characterized by the<br />
uncontrolled release of blood cells. Thus,<br />
Jaschke posited that A485, by temporarily<br />
inhibiting this leukemia-inducing region,<br />
14 Yale Scientific Magazine March 2024 www.yalescientific.org