Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Prenatal stem cell transplants may open door to organ transplants, treating genetic diseases

07.11.2002


In a finding that could open the door to future treatments for many genetic diseases such as sickle cell anemia and muscular dystrophy, researchers have produced high levels of transplanted, healthy stem cells in mice, while sharply reducing a hazardous side effect of cell and organ transplants called graft-versus-host disease.


By combining prenatal transplants of blood-forming stem cells with manipulations of blood cells after birth, researchers at The Children’s Hospital of Philadelphia achieved immune tolerance in mice, allowing donor cells to multiply without toxic side effects. The studies appear in related articles in the August and September issues of Blood.

The finding could greatly broaden the use of cell and organ transplants for genetic diseases detected before birth, such as leukemia, sickle cell disease, muscular dystrophy, and some kidney and liver disorders.

"Recent developments in genetic knowledge and technology are converging to make it likely that within a decade, nearly all human genetic diseases will be diagnosed before birth," says Alan W. Flake, M.D., director of the Children’s Institute for Surgical Science at The Children’s Hospital of Philadelphia, and senior author of both articles. "Our research may greatly expand our ability to use prenatal interventions to help the body safely tolerate treatments for genetic diseases."



Dr. Flake’s team used a prenatal procedure called in utero hematopoietic stem cell transplantation (IUHSCT). Hematopoietic stem cells develop into red blood cells, white blood cells and a variety of immune cells. The stem cells used in these studies were taken from the bone marrow of adult mice, not from human embryos.

As a disease treatment, prenatal stem cell transplants have faced a major barrier in that they have been unable to achieve high levels of engraftment – the number of donor stem cells usually does not grow large enough to overcome the effect of diseased cells. An exception to this limitation is diseases in which donor cells have a normal advantage over the transplant recipient’s cells. For instance, Dr. Flake was able to cure a child of a rare immune disease, X-linked severe combined immunodeficiency disorder (X-SCID), by using a prenatal stem cell transplant in 1996 that rebuilt his immune system.

Dr. Flake’s current studies potentially extend prenatal stem cell transplants to a broader range of diseases, by manipulating conditions to create a competitive advantage for donor cells over host cells. The IUHSCT procedure first makes the recipient’s immune system tolerant of low levels of donor cells, and then a second, nontoxic procedure after birth provides a competitive advantage for the transplanted donor cells, allowing them to multiply.

"Performing the stem cell transplant prenatally relies on features of the fetal immune system that are more receptive to transplantation," said Dr. Flake. "For instance, the immaturity of the fetal immune system makes it less able to mount an immune response against the transplanted cells." Paradoxically, the technique also relies on a strength of the fetal immune system: its healthy thymus, a gland that declines in function after puberty. The fetal thymus produces T-regulatory cells, which help to reduce graft-versus-host disease. In that disease, a life-threatening complication of cell and organ transplants, donor cells attack the patient’s tissues.

The second, postnatal step of the treatment compromises host blood cells and allows the donor cells to engraft themselves in the recipient’s bone marrow and bloodstream. Because the prenatal transplant has made the host animal tolerant of donor cells, the postnatal procedure can be less toxic than conventional treatments that use harsh chemotherapy drugs or high-dose radiation to wipe out the host’s existing immune system.

In one study, Dr. Flake used donor lymphocyte infusion (DLI) as the postnatal treatment. Currently used against some leukemias, DLI supplies lymphocytes, donated immune cells that weaken or kill host blood cells. In the other study, the postnatal treatment was low-dose full-body irradiation followed by bone marrow transplantation. Graft-versus-host disease was minimal in the DLI study, killing only one mouse out of 56, and did not occur at all in the other study.

The procedures achieved complete or near-complete chimerism – meaning that all, or nearly all, of the animal’s blood cells were derived from the donor stem cells, even though the donor animals were not matched with the recipients. "This was the first time that complete chimerism was achieved across mismatched donors and recipients without using toxic therapy," said Dr. Flake. "If this strategy can be made to work in people, there are broad implications for treating human disease."

Potential applications to disease treatment

"This approach could potentially target any diseases that are now treatable with bone marrow transplants," adds Dr. Flake. "These include blood cell diseases such as leukemias, thalassemia and sickle cell disease, as well as many inherited immunodeficiency disorders."

Beyond that, he added, the technique might also treat muscular dystrophy, an incurable genetic disease that impairs muscle development. In previous research, Dr. Flake’s team showed that stem cells transplanted in utero can develop into healthy muscle cells in mice with muscular dystrophy.

Organ transplant recipients might also benefit from the technique’s ability to make a patient’s immune system tolerant of the donated organ. "If prenatal screening predicts that a fetus would have kidney or liver failure, the prenatal stem cell transplant could prepare the immune system for a future transplant," says Dr. Flake. "A tolerized immune system would better accept an organ transplant from an unmatched donor."

Although prenatal screening is not yet widespread for many genetic diseases, he adds, currently emerging technologies will make it feasible to diagnose nearly all genetic diseases early in gestation within the next 10 years. "The combination of data from the Human Genome Project, improvements in molecular diagnoses, gene chip technology, and the ability to do molecular diagnoses of fetal cells or fetal DNA within the mother’s blood, all support early gestational diagnosis of genetic disease," says Dr. Flake.

Dr. Flake cautions that the clinical applications may be years away, but based on these results, he will further investigate stem cell transplantation in mice and then in larger animals, with the goal of translating the approach to treatments for people.

John Ascenzi | EurekAlert!
Further information:
http://www.chop.edu

More articles from Health and Medicine:

nachricht Deep stimulation improves cognitive control by augmenting brain rhythms
04.04.2019 | Picower Institute at MIT

nachricht Black nanoparticles slow the growth of tumors
04.04.2019 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Quantum gas turns supersolid

Researchers led by Francesca Ferlaino from the University of Innsbruck and the Austrian Academy of Sciences report in Physical Review X on the observation of supersolid behavior in dipolar quantum gases of erbium and dysprosium. In the dysprosium gas these properties are unprecedentedly long-lived. This sets the stage for future investigations into the nature of this exotic phase of matter.

Supersolidity is a paradoxical state where the matter is both crystallized and superfluid. Predicted 50 years ago, such a counter-intuitive phase, featuring...

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

Simple and Fast Method for Radiolabelling Antibodies against Breast Cancer

23.04.2019 | Life Sciences

Quantum gas turns supersolid

23.04.2019 | Physics and Astronomy

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>