Goodnight, Stem Cells: How Well Rested Cells Keep Us Healthy

Plenty of studies show that a lack of sleep is nothing but bad news and can contribute to a whole host of health problems like heart disease, poor memory, high blood pressure and obesity.

HSCs_Sleeping_graphic100x100

Even stem cells need rest to stay healthy

In a sense, the same holds true for the stem cells in our body. In response to injury, adult stem cells go to work by dividing and specializing into the cells needed to heal specific tissues and organs. But they also need to rest for long-lasting health. Each cell division carries a risk of introducing DNA mutations—and with it, a risk for cancer. Too much cell division can also deplete the stem cell supply, crippling the healing process. So it’s just as important for the stem cells to assume an inactive, or quiescent, state to maintain their ability to mend the body. Blood stem cells for instance are mostly quiescent and only divide about every two months to renew their reserves.

Even though the importance of this balance is well documented, exactly how it’s achieved is not well understood; that is, until now. Earlier this week, a CIRM-funded research team from The Scripps Research Institute (TSRI) reported on the identification of an enzyme that’s key in controlling the work-rest balance in blood stem cells, also called hematopoietic stem cells (HSCs). Their study, published in the journal Blood, could point the way to drugs that treat anemias, blood cancers, and other blood disorders.

Previous studies in other cell types suggested that this key enzyme, called ItpkB, might play a role in promoting a rested state in HSCs. Senior author Karsten Sauer explained their reasoning for focusing on the enzyme in a press release:

“What made ItpkB an attractive protein to study is that it can dampen activating signaling in other cells. We hypothesized that ItpkB might do the same in HSCs to keep them at rest. Moreover, ItpkB is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

To test their hypothesis, the team studied HSCs in mice that completely lacked ItpkB. Sure enough, without ItpkB the HSCs got stuck in the “on” position and continually multiplied until the supply of HSCs stores in the bone marrow were exhausted. Without these stem cells, the mice could no longer produce red blood cells, which deliver oxygen to the body or white blood cells, which fight off infection. As a result the animals died due to severe anemia and bone marrow failure. Sauer used a great analogy to describe the result:

“It’s like a car—you need to hit the gas pedal to get some activity, but if you hit it too hard, you can crash into a wall. ItpkB is that spring that prevents you from pushing the pedal all the way through.”

With this new understanding of how balancing stem cell activation and deactivation works, Sauer and his team have their sights set on human therapies:

“If we can show that ItpkB also keeps human HSCs healthy, this could open avenues to target ItpkB to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

One-Time, Lasting Treatment for Sickle Cell Disease May be on Horizon, According to New CIRM-Funded Study

For the nearly 1,000 babies born each year in the United States with sickle cell disease, a painful and arduous road awaits them. The only cure is to find a bone marrow donor—an exceedingly rare proposition. Instead, the standard treatment for this inherited blood disorder is regular blood transfusions, with repeated hospitalizations to deal with complications of the disease. And even then, life expectancy is less than 40 years old.

In Sickle Cell Disease, the misshapen red blood cells cause painful blood clots and a host of other complications.

In Sickle Cell Disease, the misshapen red blood cells cause painful blood clots and a host of other complications.

But now, scientists at UCLA are offering up a potentially superior alternative: a new method of gene therapy that can correct the genetic mutation that causes sickle cell disease—and thus help the body on its way to generate normal, healthy blood cells for the rest of the patient’s life. The study, funded in part by CIRM and reported in the journal Blood, offers a great alternative to developing a functional cure for sickle cell disease. The UCLA team is about to begin a clinical trial with another gene therapy method, so they—and their patients—will now have two shots on goal in their effort to cure the disease.

Though sickle cell disease causes dangerous changes to a patient’s entire blood supply, it is caused by one single genetic mutation in the beta-globin gene—altering the shape of the red blood cells from round and soft to pointed and hard, thus resembling a ‘sickle’ shape for which the disease is named. But the UCLA team, led by Donald Kohn, has now developed two methods that can correct the harmful mutation. As he explained in a UCLA news release about the newest technique:

“[These results] suggest the future direction for treating genetic diseases will be by correcting the specific mutation in a patient’s genetic code. Since sickle cell disease was the first human genetic disease where we understood the fundamental gene defect, and since everyone with sickle cell has the exact same mutation in the beta-globin gene, it is a great target for this gene correction method.”

The latest gene correction technique used by the team uses special enzymes, called zinc-finger nucleases, to literally cut out and remove the harmful mutation, replacing it with a corrected version. Here, Kohn and his team collected bone marrow stem cells from individuals with sickle cell disease. These bone marrow stem cells would normally give rise to sickle-shaped red blood cells. But in this study, the team zapped them with the zinc-finger nucleases in order to correct the mutation.

Then, the researchers implanted these corrected cells into laboratory mice. Much to their amazement, the implanted cells began to replicate—into normal, healthy red blood cells.

Kohn and his team worked with Sangamo BioSciences, Inc. to design the zinc-finger nucleases that specifically targeted and cut the sickle-cell mutation. The next steps will involve improving the efficiency and safest of this method in pre-clinical animal models, before moving into clinical trials.

“This is a promising first step in showing that gene correction has the potential to help patients with sickle cell disease,” said UCLA graduate student Megan Hoban, the study’s first author. “The study data provide the foundational evidence that the method is viable.”

This isn’t the first disease for which Kohn’s team has made significant strides in gene therapy to cure blood disorders. Just last year, the team announced a promising clinical trial to cure Severe Combined Immunodeficiency Syndrome, also known as SCID or “Bubble Baby Disease,” by correcting the genetic mutation that causes it.

While this current study still requires more research before moving into clinical trials, Kohn and his team announced last month that their other gene therapy method, also funded by CIRM, has been approved to start clinical trials. Kohn argues that it’s vital to explore all promising treatment options for this devastating condition:

“Finding varied ways to conduct stem cell gene therapies is important because not every treatment will work for every patient. Both methods could end up being viable approaches to providing one-time, lasting treatments for sickle cell disease and could also be applied to the treatment of a large number of other genetic diseases.”

Find Out More:
Read first-hand about Sickle Cell Disease in our Stories of Hope series.
Watch Donald Kohn speak to CIRM’s governing Board about his research.

No Fear of Rejection? Partial Stem Cell Transplant Reverses Sickle Cell Disease—even without Immunosuppressant Drugs

For those who suffer from the blood disorder sickle cell disease, there is really only one cure: a full bone marrow transplant followed by a lifetime of anti-rejection, immune-suppressing drugs. But now, researchers from the National Institutes of Health are testing an attractive alternative for the sickest patients.

Sickle cell disease gets its name from a single genetic change, or mutation, that alters the shape of one’s red blood cells.. Unlike the round cells that can pass easily through the body’s blood vessels, the sickle-shaped cells clump together, clogging up blood vessels. This leads to a lifetime of severe joint pain and, in many cases, organ damage and stroke. In this country it affects primarily African Americans.

Magnified blood sample of a patient with severe sickle cell disease.

Magnified blood sample of a patient with severe sickle cell disease.

The only cure is a bone marrow transplant, in which the patient’s own bone marrow is first depleted with chemotherapy, and replaced by the donor marrow. The patient then faces a lifetime of immunosuppressant, anti-rejection medication to prevent deadly rejection or graft-versus-host disease, a potentially fatal condition where the donor cells attack the recipient’s immune system.

But what if, instead of replacing the entirety of the patient’s bone marrow, doctors only replaced some of it? Would this mix of sickle and non-sickle-shaped cells be enough to reverse the symptoms? A clinical trial published today from the NIH research team in the Journal of the American Medical Association has some encouraging results.

As lead author Dr. Matthew Hsieh noted in today’s press release:

“Typically, stem-cell recipients must take immunosuppressants all their lives. That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”

In this study, the researchers performed partial bone marrow transplantations on 30 adults with severe sickle cell disease. After one year, they took 15 patients off the standard regimen of immunosuppressant drugs. And more than three years later, those 15 patients remain free from rejection.

These results are promising, in that a lifetime of immunosuppressants comes with its own set of negative side effects for the patient. According to the paper’s senior author Dr. John Tinsdale:

“Side effects caused by immunosuppressants can endanger patients already weakened by years of organ damage from sickle cell disease. Not having to permanently rely on this medication…means that even older patients and those with severe sickle cell disease may be able to reverse their condition.”

Indeed, the research team found that even a partial transplant—which resulted in a stable mix of both red blood cell types from donor and recipient – was sufficient to reverse the disease’s debilitating symptoms.

The results from this trial open the door to treating patients whose immune systems are already too weak—and are unable to tolerate the negative effects of a full stem cell transplant.

But even this half transplant has the risks associated with donor marrow. That is why CIRM is funding a team using a patient’s own stem cells and genetically modifying them to produce the correct version of the mutated protein. These self-transplants would be safer and open up the therapy to all patients regardless of their ability to find an immunologically matching donor. We expect a clinical trial with this approach to begin soon.

Want to know more about how CIRM-funded scientists are working toward this goal? Check out our “Spotlight on Sickle Cell Disease.”