August 2013

Reprogramming Stem Cells Offers Powerful Tool for Studying, Treating Diseases


First produced in the past decade, human induced pluripotent stem cells are capable of developing into many or even all human cell types. In new research, scientists reprogrammed skin cells from patients with rare blood disorders into induced pluripotent stem cells (iPSCs), highlighting the great promise of these cells in advancing understanding of those challenging diseases — and eventually in treating them.

“The technology for generating these cells has been moving very quickly,” said the studies’ leader, Mitchell J. Weiss, MD, PhD. “These investigations can allow us to better understand at a molecular level how blood cells go wrong in individual patients — and to test and generate innovative treatments for the patients’ diseases.”

Dr. Weiss, a hematologist and stem cell researcher, along with CHOP’s Monica Bessler, MD, Philip Mason, PhD, and Deborah L. French, PhD, published a study on iPSCs and Diamond Blackfan anemia, a rare congenital blood disorder. Another study published by Dr. Weiss and his team in the same journal on April 25 focused on iPSCs in the childhood cancer juvenile myelomonocytic leukemia.

In Diamond Blackfan anemia (DBA), a mutation prevents a patient’s bone marrow from producing normal quantities of red blood cells, resulting in severe, sometimes life-threatening anemia, which can make it difficult for researchers to discern the underlying mechanism of the disease. According to the Diamond Blackfan Anemia Foundation, there are 25 to 35 new cases of the disease a year in the U.S., with more than 90 percent of patients showing symptoms in the first year of life.

“It’s very difficult to figure out what’s wrong, because the bone marrow is nearly empty of these cells,” said Dr. Bessler, the director of CHOP’s Pediatric and Adult Comprehensive Bone Marrow Failure Center.

Programming Patients’ Cells

 In the June Blood study, the researchers removed fibroblasts (skin cells) from DBA patients and using proteins called transcription factors reprogrammed the cells into iPSCs. As those iPSCs were stimulated to form blood tissues, like the patient’s original mutated cells, they were deficient in producing red blood cells. However, when the researchers corrected the genetic defect that causes DBA, the iPSCs developed into red blood cells in normal quantities.

“This showed that in principle, it’s possible to repair a patient’s defective cells,” said Dr. Weiss, who cautioned that this finding is an early step, with further studies needed to verify if this approach will be safe and effective in clinical use.

However, he added, the patient-derived iPSCs are highly useful as a model cell system for investigating blood disorders. For instance, DBA is often puzzling, because two family members may have the same mutation, but only one may be affected by the disease. Because each set of iPSCs is specific to the individual from whom they are derived, researchers can compare the sets to identify molecular differences, such as a modifier gene active in one person but not the other.

Furthermore, the cells offer a renewable, long-lasting model system for testing drug candidates or gene modifications that may offer new treatments, personalized to individual patients, Dr. Weiss noted.

The study of juvenile myelomonocytic leukmia published in April, meanwhile, provides a concrete example of using iPSCs for drug testing, specifically for the rare and often-aggressive childhood leukemia JMML. First the study team generated iPSCs from two children with JMML, and then manipulated the iPSCs in cell cultures to produce myeloid cells that multiplied uncontrollably, much as the original JMML cells do.

They then tested the cells with two drugs, each of which able to inhibit a separate protein known to be highly active in JMML. One drug, an inhibitor of the MEK kinase, reduced the proliferation of cancerous cells in culture. “This provides a rationale for a potential targeted therapy for this specific subtype of JMML,” said Dr. Weiss.

Children’s Hospital’s human embryonic stem cell/induced pluripotent Stem Cell (hESC/iPSC) Core facility — which is directed by the studies’ co-author Dr. French — generated the iPSCs lines used in these studies. The facility’s goal is to develop and maintain standardized iPSCs lines specific to a variety of rare inherited diseases like DBA and JMML, including dyskeratosis congenita, congenital dyserythropoietic anemia, thrombocytopenia absent radii (TAR), Glanzmann’s thrombasthenia and Hermansky-Pudlak syndrome.

A long-term goal of this line of research, said Dr. Weiss, is for the iPSC lines to provide the raw materials for eventual cell therapies that could be applied to specific genetic disorders. “The more we learn about the molecular details of how these diseases develop, the closer we get to designing precisely targeted tools to benefit patients.”

The study was published in June in the journal Blood.

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