A new line of defense against sickle cell anemia in humans may have been uncovered in a new laboratory study involving mice. Universities in the U. S. teamed with another in Japan to successfully treat mice with a human sickle cell anemia disease trait.

Researchers say the process reprogrammed the cells of the mice into an embryonic-stem-cell-like state called “induced pluripotent stem” (IPS) cells, without the use of eggs. It’s claimed to be the first proof-of-principle of the therapeutic application in mice, while IPS cells have also recently been derived in humans.

The research was carried out in the laboratory of Whitehead Institute for Biomedical Research  Member Rudolf Jaenisch. The IPS cells were derived using modifications of the approach originally discovered in 2006 by the Shinya Yamanaka laboratory at Kyoto University.

ILLUSTRATION CREDIT: (Image: Tom DiCesare) Mice received reprogrammed cells by tail injections. Whitehead Institute for Biomedical Research.

The scientists studied a therapeutic application of IPS cells with the sickle-cell anemia model mouse developed by the laboratory of Tim Townes of the University of Alabama at Birmingham. Sickle-cell anemia is a disease of the blood marrow caused by a defect in a single gene. The mouse model had been designed to include relevant human genes involved in blood production, including the defective version of that gene.

To create the IPS cells, the scientists started with cells from the skin of the diseased mice. These cells were modified by a standard lab technique employing retroviruses customized to insert genes into the cell’s DNA. The inserted genes were Oct4, Sox2, Lif4 and c-Myc, known to act together as master regulators to keep cells in an embryonic-stem-cell-like state. IPS cells were selected based on their morphology and then verified to express gene markers specific to embryonic stem cells. To decrease or eliminate possible cancer in the treated mice, the c-Myc gene was removed by genetic manipulation from the IPS cells.

Next, the researchers followed a well-established protocol for differentiating embryonic stem cells into precursors of bone marrow adult stem cells, which can be transplanted into mice to generate normal blood cells. The scientists created such precursor cells from the IPS cells, replaced the defective blood-production gene in the precursor cells with a normal gene, and injected the resulting cells back into the diseased mice.

The blood of treated mice was tested with standard analyses employed for human patients. The analyses showed that the disease was corrected, with measurements of blood and kidney functions similar to those of normal mice.

While IPS cells offer tremendous promise for regenerative medicine, scientists caution that major challenges must be overcome before medical applications can be considered. First among these is to find a better delivery system, since retroviruses bring other changes to the genome that are far too random to let loose in humans.