Stem-cell-derived cells flag possible new treatment for Diamond-Blackfan anemia
February 08, 2017
Note: This study was covered by Harvard
Gazette and Harvard
First successful use of iPS cells to find drugs for a blood disease
Researchers at Boston Children’s Hospital’s Stem Cell
Research Program were able, for the first time, to use patients’ own cells to create
cells similar to those in bone marrow, and then use them to identify potential
treatments for a blood disorder. The work was published today by Science Translational Medicine.
The team derived the so-called blood progenitor cells from two
patients with Diamond-Blackfan
anemia (DBA), a rare, severe blood disorder in which the bone marrow cannot
make enough oxygen-carrying red blood cells. The researchers first converted
some of the patients’ skin cells into induced pluripotent stem (iPS) cells.
They then got the iPS cells to make blood progenitor cells, which they loaded
into a high-throughput drug screening system. Testing a library of 1,440 chemicals,
the team found several that showed promise in a dish. One compound, SMER28, was
able to get live mice and zebrafish to start churning out red blood cells.
The study marks an important advance in the stem cell field.
iPS cells, theoretically capable of making virtually any cell type, were first
created in the lab in 2006 from skin cells treated with genetic reprogramming
factors. Specialized cells generated by iPS cells have been used to look for
drugs for a variety of diseases — except for blood disorders, because of
technical problems in getting iPS cells to make blood cells.
“iPS cells have been hard to instruct when it comes to
making blood,” says Sergei Doulatov, PhD, co-first author on the paper with Linda
Vo and Elizabeth Macari, PhD. “This is the first time iPS cells have
been used to identify a drug to treat a blood disorder.”
DBA currently is treated with steroids, but these drugs help
only about half of patients, and some of them eventually stop responding. When
steroids fail, patients must receive lifelong blood transfusions and quality of
life for many patients is poor. The researchers believe SMER28 or a similar
compound might offer another option.
“It is very satisfying as
physician scientists to find new potential treatments for rare blood diseases
such as Diamond Blackfan anemia,” says Leonard
Zon, MD, director of Boston Children’s Stem Cell Research Program and co-corresponding author on the paper with George Q. Daley, MD, PhD. “This work illustrates a wonderful triumph,” says
Daley, associate director of the Stem Cell Research Program and also dean
of Harvard Medical School.
Making red blood
As in DBA itself, the patient-derived blood progenitor
cells, studied in a dish, failed to generate the precursors of red blood cells,
known as erythroid cells. The same was true when the cells were transplanted
into mice. But the chemical screen got several “hits”: in wells loaded with
these chemicals, erythroid cells began appearing.
Because of its especially strong effect, SMER28 was put
through additional testing. When used to treat the marrow in zebrafish and
mouse models of DBA, the animals made erythroid progenitor cells that in turn
made red blood cells, reversing or stabilizing anemia. The same was true in
cells from DBA patients transplanted into mice. The higher the dose of SMER28,
the more red blood cells were produced, and no ill effects were found. (Formal
toxicity studies have not yet been conducted.)
Previous researchers have tried for years to isolate blood
stem cells from patients. They have sometimes succeeded, but the cells are very
rare and cannot create enough copies of themselves to be useful for research.
Attempts to get iPS cells to make blood stem cells have also failed.
The Boston Children’s researchers were able to circumvent
these problems by instead transforming iPS cells into blood progenitor cells
using a combination of five reprogramming factors. Blood progenitor cells share
many properties with blood stem cells and are readily multiplied in a dish.
“Drug screens are usually done in duplicate, in tens of
thousands of wells, so you need a lot of cells,” says Doulatov, who now heads a
lab at the University of Washington. “Although blood progenitor cells aren’t
bona fide stem cells, they are multipotent and they made red cells just fine.”
SMER28 has been tested preclinically for some
neurodegenerative diseases. It activates a so-called autophagy pathway that
recycles damaged cellular components. In DBA, SMER28 appears to turn on
autophagy in erythroid progenitors. Doulatov plans to further explore how this
interferes with red blood cell production.
Zon and Daley have been awarded NIH funding from the
National Heart, Lung and Blood Institute’s Progenitor Cell Translational
Consortium to further explore several promising compounds identified through
The study was supported by
grants from the NIH National Institute of Diabetes and Digestive and Kidney
Diseases (R24-DK092760 and R24-DK49216), the NHLBI Progenitor Cell Biology
Consortium (UO1-HL100001) (NHLBI R01HL04880 and NIH
Alex’s Lemonade Stand; The Taub Foundation Grants Program for MDS AQ43
Research; and the Doris Duke Medical Foundation. Additional
funding came from a National Science Foundation Graduate Research Fellowship
and NHLBI 1F32HL124948-01.