New gene-based therapies for sickle cell disease rely on finding suitable mice for work

Sickle cell disease is a highly debilitating condition that affects up to 40% of the African population and patients suffer from intolerable pain, organ damage, and reduced life expectancy.

The disease is caused by mutations in the genes that make hemoglobin, the protein that carries oxygen to red blood cells, and damaged hemoglobin distorts the shape of red blood cells, causing painful blood vessels and potentially life-threatening obstructions.

However, scientists have found that increasing the production of healthy forms of this protein (usually fetal hemoglobin, which is produced only when in utero) can provide innovative treatments for these patients. I did.

Their current Disease model and mechanism In the article, Mitchell Weiss and a colleague at St. Jude Children’s Research Hospital in Memphis, USA, explored promising new therapies being developed in Weiss’s lab, edited genes and edited this healthy fetal hemoglobin in adult red. Switch on the production of blood cells.

When the treatment was tested in mice, researchers found that even if the laboratory mice had symptoms of sickle cell disease, the fetal hemoglobin gene and surrounding DNA were not properly constructed and were innovative. We have found that stem cell therapy is ineffective or even harmful to animals and raises concerns about future studies testing new gene-based therapies in these mice.

Before testing new treatments on people, scientists test them on animals, so Weiss and colleagues are new with two types of mice that carry the symptoms of sickle cell disease, the so-called “Berkeley” and “Towns.” Mice that have tried gene therapy.

First, they removed stem cells (bone marrow cells programmed to become red blood cells) from mice, modified some of the stem cell’s DNA using gene editing, and turned on the healthy fetal hemoglobin gene. Scientists then returned these reprogrammed stem cells to mice and monitored the animals for 18 weeks to see how treatment affected them.

Surprisingly, 70% of Berkeley mice died from treatment and only 3.1% of mouse stem cells activated the production of the healing fetal hemoglobin gene. In contrast, treatment activated the fetal hemoglobin gene in 57% of red blood cells in Towns mice and did not affect animal survival. However, the levels of fetal hemoglobin produced in red blood cells of Towns mice are 7-10 times lower than were seen when this approach was used in laboratory-grown human cells, a clinical sign of sickle cell disease. It wasn’t high enough to reduce.

Later, Weiss and colleagues wanted to know why this new treatment was unsuccessful in Berkeley mice, which have been used for decades to test the treatment of sickle cell disease. “I noticed that he wasn’t fully aware of the genetic makeup of these mice,” said Dr. Weiss.

Therefore, the team sequenced the hemoglobin gene and surrounding DNA in Berkeley mice and instead of having a single copy of the mutated human gene, the mouse randomly placed 22 of the mutated human sickle cell disease genes. I found that I had a disassembled copy that was mutated. 27 copies of human fetal hemoglobin that the team wanted to activate to cure sick mice.

This complex genetic composition caused fatal effects when scientists tested gene therapy in Berkeley mice. Editing multiple copies of a gene can damage the DNA. This means that researchers cannot use these mice to test and optimize this gene-editing therapy.

In contrast, Towns mice had only a single copy of the mutated human hemoglobin gene and the gene that makes human fetal hemoglobin. However, these mice may usually lack important DNA fragments that regulate the production of the human fetal hemoglobin gene.

Therefore, they were unable to produce enough of this healthy protein to relieve the symptoms of mice.

Our findings help scientists using Berkeley and Towns mice decide which to use to address specific research questions related to sickle cell disease or hemoglobin. increase. In addition, this task reminds scientists to carefully review the genetics of the mice they use to study human disease and find suitable mice for their work... “

Mitchell Weiss, St. Jude Children’s Research Hospital