New approach could make bone marrow transplants safer

June 6, 2016 by Hannah L. Robbins, Harvard Medical School

Harvard Stem Cell Institute (HSCI) scientists have taken the first steps toward developing a treatment that would make bone marrow - blood stem cell - transplantation safer and, as a result, more widely available to the millions of people living with blood disorders like sickle cell anemia, thalassemia, and AIDS.

Bone marrow transplantation currently is the only curative therapy for these blood diseases. But, for the new, transplanted to do their work, the faulty stem cells must first be "evicted" or killed. Accomplishing that requires patients endure chemotherapy and radiation—a vicious assault on the body with life-long consequences.

In a study recently published in the journal Nature Biotechnology, HSCI researchers at Harvard University and Massachusetts General Hospital (MGH), in collaboration with Boston Children's Hospital and Dana Farber Cancer Institute, have developed a non-toxic transplantation procedure using antibodies to specifically target in mice, an approach they hope will make blood for these patients far less toxic.

The new treatment removes more than 98% of blood stem cells, making it as effective as chemotherapy and radiation.

"Instead of using non-targeted drugs that have lots of collateral damage we thought we could take advantage of the precision of the immune system, in particular, antibodies," said David Scadden, MD, Co-director of HSCI, the Gerald and Darlene Jordan Professor of Medicine at Harvard University, and senior author on the paper.

As part of the immune system, antibodies naturally seek and destroy foreign agents in the body. Rahul Palchaudhuri, a postdoctoral fellow in Scadden's lab and first author on the paper, armed CD45-targeting antibodies with a payload that destroys only existing blood cells. The payload kills cells by means other than genetic destruction, in contrast to the current standard treatments.

"Antibodies are remarkably specific in what they target," said Palchaudhuri, a chemist by training, with a background in cancer research. "We can direct them to CD45, a cell marker which is exclusively expressed in the blood system. That way we avoid toxicities to non-blood tissues."

Unlike chemotherapy and radiation—which indiscriminately damage cells and tissues, healthy or otherwise—the CD45-targeting antibodies leave the thymus and the , environments critical to the formation of T cells and innate immune cells, unharmed. Animals receiving the antibody treatment were able to withstand infection that was lethal to mice treated with radiation. Currently, infections after transplant are common and may be severe, causing death in a substantial number of people.

About one in ten patients do not survive transplantation following the standard treatments. Those who do may suffer from stunted growth and intellectual development, infertility, and damaged DNA; at present, patients can only attempt a curative transplant by increasing their risk of developing cancer later.

Because of this, families and doctors often shrink from transplant options, particularly when it comes to treating children, and it will limit the extent to which the breakthroughs in gene therapy and gene editing will be applied, explained Scadden, who is a practicing hematologist at MGH and chairman of Harvard's Department of Stem Cell and Regenerative Biology.

Animals that received the antibody treatment had a broad ten-day window within which they could accept a bone marrow transplant, and individuals that did not receive a bone marrow transplant were able to fully recover without adverse effects. Furthermore, mice suffering from were successfully transplanted using the antibody method and cured of their anemia. Should the same hold true for humans, what amounts to months of recovery in a hospital bed may be replaced by an outpatient procedure, and a failed transplant would not be fatal.

"If this approach works in humans, it will really change the conversation that providers have with patients," Scadden said, especially for those "who have these underlying genetic disorders and for who the new gene-editing and gene therapy techniques are being developed."

The scientists are now trying to identify antibodies that would be effective in humans, and a company has been formed to move the work towards translation and determine which models are most useful in a preclinical setting.

"It brings precision medicine into the area of transplant in a way that hasn't been there and is needed," Scadden said.

Explore further: Dose of transplanted blood-forming stem cells affects their behavior

More information: Rahul Palchaudhuri et al, Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin, Nature Biotechnology (2016). DOI: 10.1038/nbt.3584

Related Stories

Dose of transplanted blood-forming stem cells affects their behavior

May 25, 2016
Unlike aspirin, bone marrow doesn't come with a neatly printed label with dosage instructions. However, a new study published in Cell Reports provides clues about how the dose of transplanted bone marrow might affect patients ...

Dual stem-cell transplant improves outlook for children with high-risk neuroblastoma

June 6, 2016
Children with high-risk neuroblastoma whose treatment included two autologous stem-cell transplants were more likely to be free of cancer three years later than patients who underwent a single transplant, a Phase 3 clinical ...

Newly identified genes impact how transplanted stem cells give rise to blood cells

February 16, 2016
A team of researchers led by scientists at St. Jude Children's Research Hospital is looking at ways to improve how blood-forming stem cells can be used for therapeutic interventions. The work has uncovered a group of genes ...

Blood stem cells study could pave the way for new cancer therapy

March 10, 2016
People with leukaemia could be helped by new research that sheds light on how the body produces its blood supply.

Preliminary study: Antibody therapy reduces cancer stem cells in multiple myeloma

April 15, 2016
An experimental antibody treatment decreased by half the number of cancer stem cells that drive the growth of tumors in nearly all patients with multiple myeloma, a cancer of the bone marrow and bone tissue, according to ...

UI Health validates cure for sickle cell in adults

September 16, 2015
Physicians at the University of Illinois Hospital & Health Sciences System have cured 12 adult patients of sickle cell disease using a unique procedure for stem cell transplantation from healthy, tissue-matched siblings.

Recommended for you

Scientists discover new causes of cellular decline in prematurely aging kids

March 19, 2018
In a recent paper published in Cell Reports, Saint Louis University researchers have uncovered new answers about why cells rapidly age in children with a rare and fatal disease. The data points to cellular replication stress ...

Don't blame adolescent social behavior on hormones

March 19, 2018
Reproductive hormones that develop during puberty are not responsible for changes in social behavior that occur during adolescence, according to the results of a newly published study by a University at Buffalo researcher.

Stem cells treat macular degeneration

March 19, 2018
In July 2015, 86-year-old Douglas Waters developed severe age-related macular degeneration (AMD). He struggled to see things clearly, even when up close.

Measuring neutrophil motility could lead to accurate sepsis diagnosis

March 19, 2018
A microfluidic device developed by Massachusetts General Hospital (MGH) investigators may help solve a significant and persistent challenge in medicine—diagnosing the life-threatening complication of sepsis. In their paper ...

Democratizing science: Researchers make neuroscience experiments easier to share, reproduce

March 16, 2018
Over the past few years, scientists have faced a problem: They often cannot reproduce the results of experiments done by themselves or their peers.

Human 'chimeric' cells restore crucial protein in Duchenne muscular dystrophy

March 16, 2018
Cells made by fusing a normal human muscle cell with a muscle cell from a person with Duchenne muscular dystrophy —a rare but fatal form of muscular dystrophy—were able to significantly improve muscle function when implanted ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.