Les antibiotiques sont produits sous des formes pharmaceutiques telles que des pilules acheter du diflucan
elles permettent d'injecter la quantité de préparation strictement nécessaire.
Banking on cord blood stem cells
Banking on cord blood stem cells
lion cells, whereas the lower threshold for
public banking is 1–1.5 billion. Only 8–12%
of banked units have enough cel s to transplant
New research will shed light on claims from commercial banks that an average ( 80 kg) size adult.
cord blood–derived stem cells can be used in diseases beyond
One strategy to get around this limit is to
combine two cord blood units, a procedure
hematological disorders. Sarah Webb investigates.
introduced by a team led by John Wagner at
the University of Minnesota in 1999 (ref. 1).
"Although that strategy appears to work, no
In April, University of Minnesota researchers North Carolina. The cells are less mature than one understands how or why," according to
conducted the first cord blood transplant to those from an adult donor and less likely to Kurtzberg. Typically, only one unit engrafts,
cure a pediatric patient of leukemia and HIV/ trigger an immune response.
she adds, and it's not necessarily the bigger
AIDS, only the second patient and the first
In addition, collecting cord blood is non- unit or the better matched unit. "There is a lot
child to receive such therapy. (The first patient invasive, and it makes use of tissue that of research going on trying to understand that,
received bone marrow from a CCR5 variant in hospitals would otherwise discard as medi- but no one has figured it out," she says.
2007, and ostensibly has been cured of HIV/
cal waste. Much of the motivation for and
Research presented at the American
AIDS.) Also eagerly anticipated are the results governmental support of cord blood bank- Society of Hematology meeting in December,
of two phase 2, placebo controlled trials for ing has come from the opportunity to break in Atlanta, offered conflicting results about
cerebral palsy using autologous cord blood. down treatment barriers for underserved the double-unit strategy. A retrospective
If successful, any of these trials could provide populations, says Shelley Grant, chief of study by Eliane Gluckman's group, in the
a watershed moment for cord blood–derived the blood stem cell transplantation branch Hôpital Saint-Louis in Paris, showed that
stem cells, which, up to now, have been used of the US Health Resources and Services there were fewer relapses among adults
mainly for treating hematological and selected Administration of the US Department of with acute leukemia who had received two
Health and Human Services (HRSA). Public units compared to those who had received
However, the hype surrounding these cells cord blood banks focus considerable effort single-unit transplants2. However, these
has outpaced the research into their clinical on collecting units from diverse popula- results conflict with those of a study by the
All rights reserved.
benefit. Against a rising tide of marketing tions, with the goal of increasing the likeli- Blood and Marrow Transplant Clinical Trial
from private cord cell banks that often prey on hood that patients of all ethnic backgrounds Network, presented at the same meeting3,
parental fears, a skeptical medical community will find suitable matches. With cord blood, which suggested that in acute leukemia in chil-
is encouraging parents of newborns to donate four matches out of six markers is accept- dren, an adequate single cord blood unit with
cord blood to public banks, rather than paying able, whereas matching bone marrow from a particular drug regimen to prevent graft-
for collection and storage in private ones for an unrelated adult requires seven or eight out versus-host disease (called conditioning), is
their own use. But should new research legiti- of eight markers to match. The goal, however, as effective as a double transplant.
mize the effectiveness of cord blood in cerebral is to find the best unit for the patient in terms
This might mean that how conditioning is
palsy or in other areas of regenerative medi- of both HLA match and cell quantity, says done is more important than whether a second
cine, private banking might complement public Mary Halet, recruitment director for the unit is used, says Juliet Barker of the Memorial
efforts that increasingly face a funding shortfal central region for Be The Match, part of the Sloan-Kettering Cancer Center in New York
and more stringent regulatory environment.
National Marrow Donor Program.
and a member of the University of Minnesota
team that pioneered this procedure. She notes
A ready source of hematopoietic stem cells
Giving umbilical cord blood a boost
that around the time double-cord transplants
For over 40 years, clinicians have used hema- The number of cells recovered from most were introduced, some changes were made to
topoietic stem cells derived from bone mar- umbilical cords is small, averaging 500 mil- the drugs given to patients both before and
row or peripheral blood, provided by human
leukocyte antigen (HLA)-matched family
members or unrelated donors, as a lifesav-
ing treatment for severe anemia and hema-
tological cancers (Fig. 1
). Seventy percent of
patients will not find a matching donor within
their families and must go to one of the pub-
lic donor registries; patients from minority
groups or with diverse ethnic backgrounds
often have difficulty finding a suitable match
within the adult donor registries, accord-
Number of transplants 1,500
ing to the National Marrow Donor Program
(NMDP), based in Minneapolis. Cord blood
transplants have been found to be useful in
these situations, as the requirements for HLA
matching are not as rigorous for these cells,
says Joanne Kurtzberg, professor of pediatrics
Peripheral blood stem cells
and pathology at Duke University and director Figure 1
Increasing use of cord blood in regenerative medicine. (Source: National Marrow Donor
of the Carolinas Cord Blood Bank in Durham, Program)
volume 31 NumBeR 7 JulY 2013
bers of CD34+ cells by culturing them with an
Table 1 Selected companies with products to assist with cord blood transplants
immobilized engineered Notch ligand for 16
Level of testing
days. The technique produces high yields of
CLt-008, made from adult myeloid Phase 1 for hematologic progenitor cells
cells, Delaney says, up to 200 cells for every
(San Carlos, California)
CD34+ cell they started with. In a recent
ProHema, made from modified
Phase 2, hematologic malignancies
hematopoietic stem cells from cord
paper6, they describe a phase
1 study during which they carried out double-
Stemex, cord blood with cells
Phase 3 for hematological
unit transplants using one unmanipulated unit
expanded using a copper chelator malignancies
and a second expanded unit. As with the study
and infused with unexpanded
from MD Anderson, the cells engrafted more
quickly in these patients. The modified unit
NiCord, Cord blood expanded using Phase 2 for hematological nicotinamide (NaM)
malignancies, sickle cell and MDS
engrafts at first in these patients, but after sev-
Human umbilical cord perivascular In development
eral months, the unmodified unit takes over
and provides long-term engraftment. With
the extension of the Hutchinson Center trial
to patients at other centers, Delaney says, the
after the transplant (antithymocyte globulin,
A variety of ex vivo
expansion strategies also engraftment times have dropped further to a
an anti-rejection agent and anti-inflammatory look promising to help speed engraftment and median of 11 days, which she attributes to bet-
corticosteroids were eliminated, and the even boost the cell dose. Unlike a typical cord ter selection of the units for expansion.
purine analog Fludara (fludarabine) and blood transplant where the units are used
It's unclear what types of CD34+ cells are
immunosuppressant Cell Cept (mycopheno- after minimal handling, in ex vivo
expansion, responding to these ex vivo
late mofetil) were added). But the conflicting researchers treat the cells with various chemi- says. Both stem cells and the more differen-
results between the studies might also suggest cals and/or protein factors or culture them in tiated progenitor cells express CD34 on their
fundamental differences between diseases supportive cellular environments to boost the surfaces. In the work from both MD Anderson
of children and adults and how each patient numbers of specific cell types. Researchers led and the Hutchinson Center, the cells from
group responds to cord blood transplantation. by Elizabeth Shpall at Houston's MD Anderson the modified unit engraft initially, but the
All rights reserved.
Cancer Center tried to spur expansion in unmodified cord blood unit ultimately takes
cord blood by exposing cells to a cocktail of over. That may occur because the cells from
Even with the success of double cord trans- growth factors: stem cell factor, granulocyte the manipulated unit are farther along the dif-
plants, the cost of the procedure raises con- colony-stimulating factor and thrombopoi- ferentiation pathways at the time of transplant,
cerns. In the US, the cost for just a unit of cord etin, says Chitra Hosing, who worked on the Hosing suggests, and can provide that initial
blood for transplant hovers around $40,000. clinical trials and is associate director of the support.
Hospital costs can be higher as engraftment MD Anderson Cord Blood Bank. Though they
That potential for expanded cord blood
with cord blood takes longer (21–35 days) increased cell dose, it didn't lead to a clinical cells to serve as an immune system support
than engraftment with cells from an adult benefit for patients, she says.
for patients has led Delaney and her col eagues
donor (20 days). In addition, cost calculations
Since then, the team has moved to using to pursue the development of off-the-shelf
that look only at the cost of the cord blood monolayers of mesenchymal stromal cells expansion products that don't require HLA
units and hospital stay ignore the overall (MSCs), which produce molecular cues that matching. The need to expand cord blood
long-term survival of a patient, and whether stimulate expansion in cord blood cells. At from a matched donor adds time, money and
a patient treated with a less-expensive proce- first, they used MSCs produced from the bone complexity to the procedure, so they're test-
dure relapses within a year. "If the patient does marrow of haplo-identical donors for indi- ing whether they can develop expanded cells
better long term, that cost is absolutely war- vidual patients. But as it can take up to three that don't include immune cells from fresh
ranted," says Barker.
weeks to produce those cells from donors, cord blood units that could then be frozen
But researchers are looking for ways to Hosing and her colleagues moved to treating and given with unmodified cord blood units
both improve patient outcomes and lower the unit for expansion with off-the-shelf MSCs to speed engraftment. They're currently test-
some of these costs. Researchers in Spain produced by Mesoblast, a company based in ing this idea in the clinic both for transplants
have pioneered a procedure that transplants Melbourne, Australia. After an expansion and as a supportive therapy for acute myeloid
a unit of cord blood from an unrelated donor process of 18–19 days, the expanded unit was leukemia patients treated with chemotherapy.
and peripheral blood cells from a partially transplanted into patients along with a sec-
Another ex vivo
expansion strategy may
matched donor (known as a haplo-identical ond unmanipulated unit of cord blood. In an overcome both the engraftment delay and the
donor), typically a parent, sibling or child of initial study of 31 patients, the median time cell-dose limitations in cord blood transplants.
the patient4. The peripheral blood cells serve to engraftment was 15 days compared with Gamida Cell in Jerusalem has developed a
as immune support, reducing the duration a median of 24 days observed in the control product that uses nicotinamide (vitamin B3)
of neutropenia in these patients. The Weill group5.
to expand CD133+ hematopoietic stem cells
Cornell Medical College in New York is cur-
Researchers led by Colleen Delaney and within a unit of cord blood over a period of 21
rently enrolling patients in a phase 2 study that Irwin Bernstein at the Fred Hutchinson days. In a recent phase 1/2 study, 11 patients
will compare so-called haplo-cord transplants Cancer Research Center in Seattle are also with hematological cancers received these
with double-unit transplants. Companies are looking at ex vivo
expansion by taking advan- manipulated cells, called NiCord, along with
also testing various off-the-shelf products that tage of the expression of Notch receptors on a second unmanipulated unit of cord blood.
could serve as a bridge until the cord blood the critical CD34+ stem and progenitor cel s in Engraftment occurred in a median of just over
cells engraft in a patient (Table 1
cord blood. The procedure expands the num- ten days. Unlike the other expansion tech-
volume 31 NumBeR 7 JulY 2013 nature biotechnology
niques, the manipulated unit supported long-
Box 1 Going private
term engraftment in eight of these patients. In
June, Gamida Cell will begin a fol ow-up clini-
the commercial side of the cord blood banking business is growing; market research
cal study of a single expanded NiCord unit in
company Bioinformant worldwide of roseville, Minnesota, reports double-digit growth
these patients, without the added unmodified
in the past year both in the uS and abroad in the number of companies offering banking
unit. "If you can develop a drug which is com-
services, which outpaces the growth of the economy during the same period. Morey Kraus
posed of only one cord blood unit rather than
of Perkinelmer's ViaCord of Cambridge, Massachusetts, feels the rapid growth experienced
two, then you will obviously save $40,000 in
in the last decade is attributable to increased knowledge and expanding treatments
costs," says Yael Margolin, president and CEO
regarding cord blood, although he points out that there is a low bar for entry into the field.
of Gamida Cel . Gamida Cell has also initiated
the number of cord blood units stored in private banking is outpacing that in the public
a trial on sickle cell anemia; Duke's Kurtzberg
banks. the National Marrow Donor Program reports 185,000 cord blood units currently
is co-principal investigator on this study as
available for transplant in the uS, whereas individual private banks report more than that
well as the one on hematological malignancies.
in their own collections, a testament to their marketing skill. ViaCord, for example, has over 300,000 units (up from only a few thousand units in 2000), Cord Blood registry of
Economic and regulatory challenges
San Bruno, California, 400,000. the discrepancy stems from the fact that public banks
Public cord blood banking in the US is sup-
will store only units of a certain size. Hence, much of the donated cord blood—some say
ported through a combination of government
as much as 70%—is discarded. In contrast, private banks store all-comers, and annual
grants, private donations and fees received for
storage fees help defray the processing costs. "without annual storage fees it would be
cord blood units as they are distributed for
difficult to justify the business bases on current charges for processing cord blood units,"
transplant. HRSA provides contracts to sev-
eral organizations that coordinate bone mar-
the impact on clinical medicine is in the eye of the beholder. Success rates of
row and cord blood donations. The National
transplants hover around 90% from commercial banks (one year survival) whereas the
Marrow Donor Program coordinates the cord
National Marrow Donor Program reports one year survival in the 70% range, (though for
blood registry that allows physicians to find
non-malignant indications only). However, the commercial banks provide services to
suitable cord blood units for patients from
families, where, given the high probability of having a match, engraftment rates are better.
public banks in the US or in other countries.
tension between commercial and public banking is only going to intensify if the
All rights reserved.
HRSA also supports 13 public banks in the US
treatable conditions expand into more common childhood diseases. Banks, public and
as part of the National Cord Blood Inventory.
private, list upwards of 80 diseases as being treatable, many of them quite rare. with that in mind, all the professional societies advise against private banking, based on the
The funding was set up through the 2005
small probability that a transplant would be needed, unless the family has a medical
Stem Cell Therapeutic and Research Act
condition that could be treated with a transplant. estimates of lifetime use vary somewhat
and its 2010 reauthorization. "Roughly 40%
depending on how it is calculated, but a generally accepted value for the likelihood of
of what was authorized was appropriated so
having a transplant by age 70, based on actual usage data collected from 2000 to 2003,
far," says Kurtzberg. With so many continu-
is 1 in 217 (ref. 8), although at age 20 it's considerably lower, 1 in 1,666. However, with
ing resolutions in the federal budget in recent
more common diseases like cerebral palsy (1/500 births) or autism (1/88 births), both of
years, she says, the preprogrammed funding
which are under study, the calculus will clearly change for private versus public banking,
increases that were part of the initial legisla-
favoring private storage.
tion have not been put in place. In 2012, $11.9
andrew Pecora, chief medical officer of New York-based NeoStem says, "the real issue
mil ion from HRSA went to the National Cord
is what happens tomorrow. [the potential for umbilical cord banking in emerging diseases]
Blood Inventory; the law authorizes $23 mil-
isn't discussed enough. Discouraging people with means from private banking is equally
lion per year to be appropriated for the collec-
bad as promoting it. In five years, it will be too late."
tion and maintenance of cord blood in fiscal
years 2011 through 2014.
The cord blood banking process is expen- That led to the initial investigational new drug requirements remain available for transplant
sive, which contributes to the high cost of applications for banking cord blood units.
under an IND during this transitional period.
each transplant unit. Donor mothers com-
But in 2009, FDA gave public banks two
A by-product of this will be to standardize
plete a questionnaire about their medical years to apply for a biological license appli- industry, says Karen Taylor, medical director at
history, with the idea of eliminating the risk cation to distribute minimally manipulated StemCyte in Covina, California, which banks
of infectious disease, such as hepatitis, and cord blood for established uses, Rubinstein both public and private cord blood units. The
avoiding genetic risks that might be manifest says. (Products that are manipulated or being new regulations may help with quality control,
in the recipient. For example, Halet says, if tested in experimental therapies require an but they are also putting a financial squeeze on
both parents have had cancer, a public bank investigational new drug application (IND)). the public banks. It's not clear that all of them
won't collect the unit. Units are also screened Those new procedures include more detailed will be able to afford the new FDA licensing
for conditions such as sickle cell anemia and questionnaires for the mothers who donate procedures. "[The process of obtaining licen-
thalassemia; the units are carefully collected, cord blood and more stringent requirements sure] was literally a three-year, incredibly
tracked and stored under specified conditions. for the handling of the cord blood units within intensive, incredibly expensive process," says
The US Food and Drug Administration (FDA) licensed banks7. The enforcement of FDA Kurtzberg, whose bank recently completed the
first started regulating cord blood in the mid- oversight has raised concerns that only the new FDA licensing. "The value added is not
1990s, says Pablo Rubinstein, vice president larger clinical centers will be able to afford proportional to the resources that are required
and program director of the New York Blood the cost and negotiate the cumbersome and and it [has] complicated the whole process of
Center's National Cord Blood Program, the complex process of liaising with the FDA. banking, made it much more expensive with
first public cord blood bank, started in 1992. Cord blood units banked before the new very little impact on the final product."
volume 31 NumBeR 7 JulY 2013
The future of banking
Rubinstein. "And if you do, and you tell them, focused on taking care of the mother and the
In comparison to public centers, private banks ‘well, I also want to use your money to sup- infant, who might be very sick, and can't always
have built a profitable business—$4.5 billion in port the public banking', then, of course, that's attend to saving the cord blood, too. "If our
2010 according to BCC Research in Wellesley, fine," he says.
studies or other studies with autologous cord
Massachusetts—on the basis of the fees paid
StemCyte's hybrid model of storing both blood show benefits in childhood diseases, then
by parents for banking cord blood for use by public and private units of cord blood provides there may be a different algorithm or paradigm
family members. Most researchers in the cord an example of how the two models can exist for banking," Kurtzberg says. Hypothetical y,
blood community remain skeptical of purely side by side. The accreditation procedures and parents might be able to donate cord blood to
private banks, in part because of the market- FDA oversight are similar for both the pub- a public bank but have the unit sequestered for
ing pitch to parents that is heavy on promises lic and private units at StemCyte, according a period of time, until it became clear that their
but short on actual benefits for their children. to Taylor. The differences come from the end child didn't need it, she says.
"Most private banks are just focused on mak- use of the cord blood, she says, within a fam-
Rubinstein adds, "In the future, we hope the
ing money, marketing, or finding ways to ily rather than for the general public. Thus, all need to develop personalized cel ular therapy
compete with one another to get parents to private units are banked, regardless of size or may occur, and, in that case, having your cord
use them over some other private bank. They family history.
blood stored away would be a remarkable
really have not demonstrated earnest efforts
or investments in research. And they haven't Banking on it
Sarah Webb, Chattanooga, Tennessee
even demonstrated earnest interest in quality," Eventual y, with further research, like the trial
on HIV/AIDS and others on genetic diseases 1. Laughlin, M.J. et al. N. Engl. J. Med. 344
But the financial squeeze being experienced like cerebral palsy, the thinking on public versus 2. rocha, V. et al.
abstract 2342, presented at the
by public banks may point to a role for pri- private banking may evolve (Box 1
54th annual Meeting and exposition of the american
vate banking, which in partnership with pub- and her col eagues are also working on autolo-
Hematology association, atlanta. December 9, 2012.
3. wagner, J.e. et al.
abstract 359, presented at the
lic banks, could provide financial support. gous cord blood as a way to facilitate repair after
54th annual Meeting and exposition of the american
However, it could be complicated as public brain injury. They're currently studying chil-
Hematology association, atlanta. December 10, 2012.
4. fernandez, M.N. et al. Exp. Hematol. 31
banks might be uncomfortable associating dren with hypoxic-ischemic encephalopathy
with what they consider unsavory market- and hypoplastic left heart syndrome, which puts 5. de Lima, M. et al. N. Engl. J. Med. 367
All rights reserved.
ing tactics employed by some private banks. children at risk for stroke and hypoxic injury.
6. Delaney, C. et al. Nat. Med. 16
, 232–236 (2010).
"In my opinion, there is nothing wrong with One chal enge with this treatment approach is 7. allison, M. Nat. Biotechnol. 30
, 304 (2012).
doing private banking provided you tell peo- that it requires a baby's own cord blood, and 8. Nietfeld, J.J. et al. Biol. Blood Marrow Transplant. 14
ple exactly what it is that you're doing," says in the delivery room, doctors and nurses are
volume 31 NumBeR 7 JulY 2013 nature biotechnology
Open Journal ofClinical & Medical Volume 2 (2016) Issue 11 Case Reports Low-Resolution Electromagnetic Tomography (LORETA) of changed Brain Function Provoked by Pro-Dopamine Regulator (KB220z) in one Adult ADHD case Bruce Steinberg; Kenneth Blum*; Thomas McLaughlin; Joel Lubar; Marcelo Febo; Eric R. Braverman; Rajendra D Badgaiyan
‘Reflection' Gold Show Garden call of the wild A sophisticated palette with wispy grasses, including Panicum ‘Heavy Metal' and P. virgatum, creates a carefully orchestrated wild and casual planting style for this design. Silver and white, with accents of pink and yellow, contrasts with the boathouse, which is clad with Oregon timber that has been burned to create