NIH Grants Will Advance New Treatments for Blood Disorders

February 17, 2010 — The new decade may herald an era of cell therapy — treating human diseases by delivering highly specific beneficial cells. In the wake of an NIH decision late last year permitting federally funded researchers to use new lines of human embryonic stem cells, the door has opened more widely to stem cell research.

Anyone who has ever undergone a bone marrow transplant has received a type of cell therapy, but current progress in stem cell research holds the potential of precisely controlling cell development for a broader variety of clinical treatments than ever before.

Grants focus on cellular therapy research

Two large federal grants recently awarded to The Children's Hospital of Philadelphia will advance the frontiers of research into cellular therapies. Both programs aim to engineer human cells into new generations of cells and tissues for patients suffering from blood diseases, cancer and, likely, a greater range of other disorders.

Grant one: Improving platelet supplies for hematology and oncology patients

The first grant focuses on developing human embryonic stem cells (hESCs) to improve platelet supplies for hematology and oncology patients, as well as using platelets to deliver customized proteins to injured blood vessels. 

"Having a larger and higher-quality supply of platelets will benefit many patients," said Mortimer Poncz, MD, chief of Hematology at Children's Hospital, and co-principal investigator of the $16.8 million, seven-year grant entitled, "Embryonic Stem Cell-Derived Platelets as Cellular Therapeutics." The National Heart, Lung and Blood Institute, part of the National Institutes of Health, issued the grant under a new initiative, the NHLBI Progenitor Cell Biology Consortium.

Platelets are naturally occurring blood cells that help control bleeding and assist in wound healing. Patients receiving chemotherapy and bone marrow transplantation depend on transfusions of platelets to restore levels depleted by their treatments. However, the donor supply is limited, and after multiple transfusions, patients may develop antibodies that attack the donated platelets.

Generating platelets from human embryonic stem cells

Under the platelet grant, awarded jointly to Children's Hospital and the Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, researchers will pursue a novel approach —generating platelets from human embryonic stem cells (hESCs). Such cells — derived from human embryos fertilized in vitro fertilization clinics and donated for research purposes — are capable of developing into every type of tissue in the body. The Children's Hospital group, under Poncz, will focus on generating platelets and their precursor cells from hESCs in laboratory studies.

At Children's Hospital, two project leaders who are prominent stem cell researchers recently recruited to the Hospital's Center for Cellular and Molecular Therapeutics, directed by gene therapy pioneer Katherine A. High, MD, Paul J. Gadue, PhD, and Deborah L. French, PhD, will lead important components of the overall program. Another project leader in the platelet grant, Mitchell Weiss, MD, PhD, also leads a second NIH-funded grant for stem cell research (see grant two.) Children's Hospital has established a new core facility, the Human Embryonic Stem Cell Core, to supply cells for their studies.

Developing reagents that will stimulate patients' existing precursor cells to develop into platelets

The Washington State team, under co-principal investigator Beverly Torok-Storb, PhD, will rely on its expertise in stem cell transplants and animal studies to develop reagents to administer to patients that will stimulate the patients' existing precursor cells to develop into platelets.

Customizing platelets as drug delivery vehicles

In addition to boosting the supply of platelets to carry out their usual biological roles, the researchers also seek to customize them as drug delivery vehicles. In mouse studies, for instance, Poncz's team previously treated the bleeding disorder hemophilia by loading platelets with the clotting factor that is deficient in that disease.

"In addition to investigating platelets for treating hemophilia in people, we will investigate their potential role in delivering other bioactive proteins to sites of vascular injury," said Poncz. "For instance, platelets might deliver an enzyme called urokinase to selectively disintegrate blood clots."

Grant two: Creating pluripotent stem cells (giving cells the capacity to develop into other types of cells)

A separate grant from the NHLBI also supports stem cell research, but focuses on a more recently discovered type of cell. This two-year, $997,000 grant was awarded to hematologist Mitchell Weiss, MD, PhD, The Grand Opportunity (GO) Grant, funded by the American Recovery and Reinvestment Act, is part of an NHLBI program to support novel research designed to quickly advance an area of biomedicine in significant ways.

Manipulating induced pluripotent stem cells into becoming blood-forming cells

Scientists demonstrated in 2007 that they could reprogram human somatic cells (the vast majority of cells that are not sperm or egg cells) into a pluripotent state — the capacity to develop into other types of human cells. In this project, Weiss and colleagues will manipulate induced pluripotent stem cells (iPSCs) into becoming hematopoietic, or blood-forming, cells.

"These cells represent a potentially remarkable tool for custom-fitting new tissue to an individual patient," said Weiss. "Because they originate from an individual patient's cells, they will not be rejected as foreign by the patient's immune system." But much work remains to be done in fully characterizing how iPSCs develop, and in understanding how they may differ from both hESCs and from typical blood cells.

Understanding how blood disorders develop

Weiss will also investigate iPSCs as a powerful new model system for understanding how blood disorders develop. "Many blood diseases are difficult to study in patients, in terms of the exact mechanisms by which cells develop abnormally," said Weiss. "We will investigate iPSCs in models of two pediatric disorders, with the goal of using our improved knowledge of cell biology to devise treatments."

Weiss's group will focus on blood diseases associated with Down syndrome. Children with Down syndrome (trisomy 21) are at higher risk for transient myeloproliferative disorder, a precursor of leukemia, as well as for acute megakaryoblastic leukemia. Using animal models, the researchers will stimulate iPSCs to mimic disease processes seen in Down syndrome, in hopes of discovering ways to prevent these forms of leukemia.

Developing tissue banks for specific diseases

A third goal of Weiss's project is to collect tissues from patients, then reprogram their cells into iPSCs and develop them into tissue banks for specific diseases. In this effort, his team will concentrate on a genetic blood disorder called Diamond Blackfan anemia.

Weiss's team at Children's Hospital will partner with scientists at two other institutions in the region: Pennsylvania State University, in State College, PA, and the Coriell Institute for Medical Research, in Camden, NJ.

"The successful completion of these grants was in large part based on the recent establishment of the Human Embryonic Stem Cell Core at Children's Hospital," said Poncz. "These two grants illustrate the promising future that stem cell biology holds, not only for research purposes and for hematologic and oncologic disorders, but for a wide range of diseases that presently have suboptimal therapies. The future of stem cell therapy may be limited only by our imagination."

Published on in CHOP News