Ahmedabad-based institutes get patent to use stem cells in kidney transplant

According to an article IndianExpress.com, an international
patent has been issued to the G R Doshi K M Mehta Institute of Kidney Diseases
and Research Centre (IKDRC) and Dr HL Trivedi Institute of Transplantation
Sciences (ITS) from Ahmedabad, Indian for utilization of stem cells in treatment
of patients having undergone kidney transplantation.  Given that we could not
find a patent number written in the article, as well as the fact that
"International Patents" do not exist, we presume the authors meant a provisional
patent having international priority under Paris Convention, or a Patent
Cooperation Treaty (PCT) application. 

The subject matter discussed is the use of stem cells to
circumvent the need for immune suppression during transplantation.  While immune
suppressants such as cyclosporine, rapamycin, and FK-506 have saved many lives
by making transplantation possible, they have numerous side effects associated
with their long-term use.  These include increased risk of cancer, higher number
of bacterial/viral infections, and possibility of kidney failure.  The work
discussed in the article uses the ability of stem cells to "immune modulate" and
therefore inhibit rejection.  A video describing stem cell mediated immune
modulation may be seen at this link

http://www.youtube.com/watch?v=ECi2uBSSQg8
.  

Dr Aruna Vanikar, Head of Pathology, Lab Medicine,
Transfusion Services and Immuno hematology department, IKDRC-ITS, who according
to the article recently received the patent, stated, "We have been working on
the use of stem cells since 1998. The study involved several phases. When a
patient undergoes kidney transplant, he/she might face difficulties, including
complete rejection. To suppress that, several drugs are used…Sometimes, the body
also reacts to high dosage of drugs. With this patent, patients will not have
any such complications. The stem cells would comprise mesenchymal cells
generated from the donors’ fat, and haematopoetic stem cells taken from donors’
bone marrow and blood. These cells are infused in the recipients’ liver, as it
is considered the most tolerogenic organ of the body
."

While the article did not provide technical details, we
found on

www.pubmed.com
some of Dr. Vanikar’s work.  A recent publication: Effect of
co-transplantation of mesenchymal stem cells and hematopoietic stem cells as
compared to hematopoietic stem cell transplantation alone in renal
transplantation to achieve donor hypo-responsiveness. In the journal Jan 19th
edition of the International Urology and Nephrology Journal described the
reduction of immune suppressant dosage by administration of bone marrow and fat
derived stem cells.  Another paper from the same group described the reduction
of immune suppressant dose by a similar stem cell protocol, termed the
"Ahmedabad tolerance induction protocol".  It will be interesting to see if
these early clinical results can be translated into Phase III placebo controlled
trials.  Commenting on the "tolerance induction protocol" Dr Aruna Vanikar said:
"With modification in Ahmedabad tolerance induction protocols for
transplantation without conventional immunosuppression, the results are
rewarding. Secondly, the incidences of acute and chronic rejection and
recurrence of basic disease have decreased."

Coach’s fight a team effort

Sam Harrell is a well-known Ennis football coach and father of Texas Tech’s former quarterback Graham Harrell. Steve Betik has worked in construction for decades. Both of them suffer from multiple sclerosis. When they asked the Ennis chiropractor Dr. William Davis about using stem cells for their condition, his reaction was that it would be expensive, but if they wanted to go for it, he would help raise the needed funds. Both of them have registered for an experimental stem cell therapy offered in Central America by Cellmedicine. This is the same stem cell treatment that allowed Texas Fort Worth Police Sergeant Preston Walker, a patient with multiple sclerosis be able to
return to work after failing to respond to the medication given by his neurologist.

Treatment for multiple sclerosis generally addresses symptoms, but when conventional approaches stop inducing responses, there are very little options left. One area of active investigation has been stem cell therapy. Although very new, a small three-year study by the Northwestern University School of Medicine concluded last year that stem cell transplants from the patients’ own bodies might help control or even reverse symptoms.

Unfortunately, FDA approval of such methods, even if documented in larger research, is years away. Specifically, three phases of clinical trials have to be conducted. Phase I involves testing of safety. Phase II clinical trials
test whether there is a therapeutic effect, however these are “unblinded” in that the patients know that they are receiving an experimental treatment, thus the possibility exists of placebo effect. Phase III clinical trials are performed at multiple hospitals in a “double blinded” manner so that neither the doctor, nor patient knows whether they are receiving the treatment or the placebo. At present stem cell therapy for multiple sclerosis has only reached
Phase I/II clinical trials.

Companies such as www.cellmedicine.com offer stem cell therapy based on the same science and medical practices used in the United States. To date over 200 patients with multiple sclerosis have been treated by Cellmedicine, however they openly state that the procedure is experimental. This did not deter Sam Harrell and Steve Betik.They are scheduled to fly together in June to the Cellmedicine clinic in Central America, where Harrell is expected to remain two weeks; Betik, a month.

In order to raise funds to support their treatment, the Ennis football boosters club, in conjunction with the town’s chamber of commerce, is hosting a dinner and auction April 10. Davis and others hope that any excess funds they raise through the Foundation for Hope will be applied to an annual fundraiser for anyone with special needs.

“We’re like babies crawling,” Davis said of their efforts. “Who knows what the future will hold?”

Patients interested in learning more about Cellmedicine can go to the website www.cellmedicine.com or view videos at www.youtube.com/cellmedicine

Adult Stem Cells Healing Hearts

Adult stem cells are being more and more used in patients
to achieve effects.  In the treatment of patients with heart failure, Dr. David
Prentice, discussed two studies in which adult stem cells appear to have some
benefit. 

The first study was the result of a Brazil-Florida joint
effort in which it was discovered that adult stem cells injected directly into
the heart could relieve angina. These data are not all that surprising given
that the first use of stem cells for heart failure involved a similar injection
procedure in Japan more than a decade ago.   Stem cell administration for
cardiac conditions has been performed in numerous clinical trials, here is a
link to a video on a previously published Phase III study in patients who
previously had a heart attack

http://www.youtube.com/watch?v=flv0RmzPyLU

In the current study eight patients were received the stem
cell treatment and according to the principle investigator Dr. Nelson Americo
Hossne, Jr, all of the patients treated exhibited some degree of improvement. 
The study suggested that the patients improved through stimulation of production
of new blood vessels.  Furthermore, the authors believed that the cells and the
procedure used to administer them are safe and effective. 

Dr. Hossne stated "For our patients, angina symptom
relief began as early as three months post-procedure with continuing improvement
through the twelfth month and sustained improvement past 18 months. Symptom
relief improved in all patients, suggesting that the effect is sustained, not
transitory
."

The second study that Dr. Prentice discussed is from a
Chinese group in which the protein apelin was demonstrated to have an effect on
the ability of cardiac regenerative mechanisms.  In the study, 20 heart failure
patients were treated with their own bone marrow, 20 received placebo, and 20
healthy patients were compared for control.  All twenty of the heart failure
patients treated with adult stem cells showed significant improvement in cardiac
function within 21 days of treatment, while the standard medication patients
showed no improvement. The patients who received stem cells demonstrated a
significant increase in levels of apelin, which correlated with the recovery of
cardiac function.

Dr. Amit Patel, a world-recognized stem cell pioneer,
professor at University of Utah School of Medicine and an Editor of the journal
in which the papers were published stated: "Both studies demonstrate a
possible mechanistic approach in a clinical trial. These important findings
further enhance the understanding of the use of bone marrow derived cell therapy
for the treatment of cardiovascular disease
."

Fat May Serve a Purpose in Stem Cell Research

Scientist Dr. Joseph Wu at the Stanford University School
of Medicine has recently published a new and improved method to generate stem
cells "artificially".  For almost a decade there has been substantial
controversy regarding the use of embryonic stem cells, with the debate becoming
socially and politically focused as opposed to based on science: one camp
believing that embryonic stem cell research must be supported at all costs, the
other camp believing that adult stem cells can do anything that embryonic stem
cells can do, so there should be no research performed in this area.  This
debate became somewhat irrelevant when the Japanese group of Yamanaka discovered
a method of "dedifferentiating" adult cells into cells that appear at a
molecular and functional level similar to embryonic stem cells.  These
"artificial" stem cells, called inducible pluripotent stem cells (iPS) have
several unique properties:  They don’t need to be extracted from embryos; they
can be made from the same patient that they will be used on; and the methods of
manufacturing can be relatively standardized. 

To date these cells have been demonstrated to be capable of
generating not only every tissue in the body tested, but they also can improve
disease conditions in animal models ranging from heart attacks, to liver
failure, to bone marrow reconstitution.  Unfortunately the biggest problem with
iPS cells is that they are difficult to generate.  In order to understand this,
it is important to first mention how the cells are made.  Adult cells have the
same DNA blueprint as embryonic stem cells.  However in adult cells certain
portions of the DNA are not used to make proteins.  So in liver cells the DNA
that encodes for proteins found in the skin is "silenced" or "blocked" from
making proteins by various chemical modifications that occur as a cell is
maturing.  Embryonic stem cells are considered "blank slate" cells because the
DNA is capable of expressing every protein found in the body.  In order to make
an adult stem cell "younger" so as to resemble an embryonic stem cell, it is
necessary to somehow reprogram the DNA in order to allow it to express every
gene.  So how would one go about doing this? There is one biological condition
in which adult cells take the phenotype of younger cells.  This is in cancer. 
This is the reason why some types of cancer start expressing proteins that other
cells normally produce.  For example certain liver cancers can produce insulin,
even though liver cells do not produce insulin.  The concept that certain cancer
genes can evoke a "rejuvenation" of adult cells was used by Yamanaka as a
starting point.  His group found that if you insert the oncogene c-myc, together
with the stem cell genes Nanog, Oct-4, and SOX-2 skin cells will start to look
like embryonic stem cells.  If these cells are placed on top of feeder cells
then they can be expanded and used as a substitute for embryonic stem cells.

The current problem with wide-scale use of this approach is
that insertion of the various genes into the cells requires the use of viruses
that literally infect the cells with the foreign genes.  Not only can the
viruses cause cancer, but also the genes administered can cause cancer because
they are oncogenes.  The other hurdle is that generation of iPS cells is a very
inefficient process.  It takes approximately 2-3 months to generate stable
cells, and these cells are usually generated from approximately 1 out of
100-300,000 starting cells.  We previously discussed advances that allowed for
uses of non-hazardous means of inserting genes into cells to make iPS

http://www.cellmedicine.com/thomson-safer-ips.asp
, in this current article
another approach was described to increase efficacy.

Scientists used as starting population not skin cells,
which are considered substantially differentiated, but instead used fat derived
stem cells.  This type of stem cell is very much a mesenchymal stem cell

http://www.youtube.com/watch?v=qJN2RyBj78I
and possesses ability to
transform into different tissues already.  Thus by starting with a cell that is
already more "immature", scientists have been able to increase the rate of iPS
generation, as well as, alleviate the need for the oncogene c-myc.

Other approaches being investigated on increasing
generation of iPS cells include use of chemicals that affect the DNA structure
such as valproic acid.  This is interesting because simple administration of
valproic acid on bone marrow stem cells has been demonstrated to increase their
"stemness"

http://www.youtube.com/watch?v=3Hc4LCUOSiA
.

Although we are still far from the day when
individual-specific stem cells will be available for widespread use, we are
getting closer to this dream at a very fast pace.

Stem Cells for HIV?

HIV infection causes its devastating effects on patients by
destruction of the CD4 T helper cell and macrophage component of the immune
system.  Entry of the virus into these cells occurs via binding to the molecules
CD4 and CCR5.  Interestingly a group of patients who appear to be resistant to
HIV infection have a mutation in the CCR5 protein.  Studies conducted on these
patients have demonstrated that the mutation in CCR5 results in resistance to
infection, while other components of the immune system of these patients are
intact.  Thus one possible method of treating HIV would be if somehow one could
induce the CCR5 mutation that is protective from HIV into the immune cells of
patients.  It is very difficult to selectively mutate established immune cells,
however, one possibility would be if one could induce such a mutation in stem
cells, and then administer the stem cells to the patient so that they
"differentiate" into immune cells.

Scientists from the Department of Microbiology, Immunology
and Molecular Genetics, at the David Geffen School of Medicine, University of
California at Los Angeles have started figuring methods of doing this. 
Specifically, a new technology called "RNA Interference" was used to selectively
block expression of the CCR5 gene on stem cells.  RNA interference is a process
that is normally used by mammalian cells to protect themselves against viruses. 
Specifically, RNA is found only as a single strand in mammalian cells.  Double
stranded RNA is found only in viruses.  When a mammalian cell recognizes double
stranded RNA it believes that a viral infection is occurring and two processes
are triggered.  The first is gene-nonspecific.  Regardless of what is coded in
the double stranded RNA, the cell starts to produce the protein interferon,
which blocks other cells from being infected, as well, the cell alters various
metabolic activities and enters a quiescent state.  The second process is
gene-specific, in that the cell will destroy any other RNA that resembles what
is encoded in the double strand.  While the first effect is useful for
inhibition of viral infections, it is non-specific and causes general toxicity
when administered at high enough levels to people or animals in order to elicit
an effect.  Thus a Nobel Prize was awarded in 2006 to Fire and Mello when they
discovered that by administering pieces of double stranded RNA shorter than 21
nucleotides, the selective gene-silencing effect could be induced in absence of
the non-selective "interferon effect".

In their recent paper, Liang et al used RNA interference to
block expression of the CCR5 gene on stem cells that are capable of giving rise
to both CD4 T cells, as well as macrophages.  They demonstrated that
gene-blockade was passed on to the progeny of the stem cell, and that the newly
generated cells were resistant to HIV infection in vitro.

In contrast to using stem cells for hematopoietic
transplantation, in which depletion of the original recipient cells is required,
the use of genetically engineered stem cells for treatment of HIV would not
require such myeloablation since the HIV infection will naturally be killing the
non-manipulated cells.

Hope Through Stem Cell Therapy

Mary Posta suffers from multiple sclerosis, a debilitating
disease that progressively degenerates the nervous system of its victims through
stripping away the insulator proteins surrounding the nerves called myelin.

In January of this year Mary Posta completed raising funds
to be treated by Cellmedicine in Central America using stem cells and returned
from treatment feeling "really good".  Specifically, after a month spent at
Cellmedicine, she stated "I can walk and talk better, and there are other
things." She adds "My memory seems to be better. I’m moving faster on thinking
and talking, and I have a lot more energy. I used to have to take sleeping pills
but have not had to start taking them again."

The stem cell therapy comprises of an intensive four-week
program of stem-cell and physical therapies.  The stem cells used are from adult
sources and therefore are not subjected to the ethical controversy associated
with other types of stem cells such as fetal or embryonic stem cells.

Cellmedicine has previously published results of the first
three multiple sclerosis patients in a peer reviewed medical journal which can
be found at this link

http://www.translational-medicine.com/content/pdf/1479-5876-7-29.pdf

The approach used involves administration of the cells
purified from the fat of the patients.  These cells contain two types of stem
cells, one called mesenchymal and the other called hematopoietic.  Additionally,
cells extracted from fat include alternatively activated macrophages and T
regulatory cells.  At a theoretical level these cells may be mediating their
effects as follows: 

Mesenchymal stem cells are known to inhibit multiple
sclerosis when administered in animal models of the disease, as seen in this
video

http://www.youtube.com/watch?v=D2RIuCc5h0A
.  The video discusses one
mechanism by which mesenchymal stem cells achieve this effect, particularly
through induction of an enzyme called indolamine 2,3 deoxygenase, which is
responsible for shutting down autoreactive T cells.  Since multiple sclerosis is
a disease in which T cells are mediating destruction of the myelin sheath,
suppression of autoreactive T cells is theoretically beneficial.  Additionally,
mesenchymal stem cells are known to produce various growth factors that increase
ability of the body’s own cells to repair themselves.  Furthermore, some studies
have suggested that mesenchymal stem cells themselves are capable of
differentiating into oligodendrocytes and Schwann cells, which produce myelin,
as well as into brand new nervous system tissue. 

Hematopoietic stem cells are conventionally known as
the cells that are responsible for the therapeutic effect of bone marrow
transplantation.  That is, these are the cells that produce all the blood cells
in the body.  More recent studies have shown that hematopoietic stem cells, such
as CD34 positive cells,  are capable of producing growth factors such as IGF-1,
these are capable of protecting various cells in the body from premature cell
death.  Additionally, there are some studies that suggest CD34 cells are capable
of regenerating injured nervous system tissue.

Alternatively activated macrophages comprise a
subset of the immune system cell classically known as the "big eater".  While
conventional macrophages are involved in protecting the body from disease by
eating pathogens, as well as producing inflammatory stimuli, alternatively
activated macrophages are involved in healing of damaged tissue.  It is known
that alternatively activated macrophages generate substances such as
interleukin-10 that shut down ongoing immunological/inflammatory reactions, as
well as assist in tissue healing.

T regulatory cells resemble the "anti-matter" of T
cells.  The body has two parallel universes of T cells.  The conventional T
cells are responsible for attacking everything that does not belong to the
body.  That is, conventional T cells recognize and kill bacteria, viruses, and
other pathogens.  On the other hand, T regulatory cells recognize everything
that "belongs" to the body.  For example, there are T regulatory cells in the
body that recognize myelin.  The difference between T regulatory cells and
conventional T cells is that T regulatory cells do not "kill" but instead
prevent what is being recognized by conventional T cells from being killed.  In
other words the T regulatory cells serve as a backup mechanism for the immune
system so that in situations such as multiple sclerosis, where the conventional
T cells are attacking something that they should not be attacking, the T
regulatory cells try to inhibit that attack.  Unfortunately in multiple
sclerosis, by the time the disease is clinically detected, the T regulatory
cells are not exerting their effects for reasons some known and some unknown. 
Adipose tissue contains high numbers of T regulatory cells, which are more
potent than T regulatory cells found from other tissues in the body.  This is
explained in this video, which discusses a publication from Harvard Medical
School
http://www.youtube.com/watch?v=rEJfGu29Rg8.

Given the potent combination of stem cells, and other
therapeutic cells, found in fat tissue, it is interesting that the company
Vet-Stem has already commercialized the procedure of using fat-derived cells for
treatment of companion animals.  Here is a video discussing some of Vet-Stem’s
technologies
http://www.youtube.com/watch?v=hEkSJo3CmPc .

Use of fat stem cells in patients with multiple sclerosis
has been previously reported in numerous other media venues:

CBS News:

http://www.youtube.com/user/cellmedicine#p/u/24/wIcUaKZWOSE

Fox 4 News:
http://www.youtube.com/user/cellmedicine#p/u/25/1j1F57olCdI

Texas Channel 8 News:
http://www.youtube.com/user/cellmedicine#p/u/21/r_mOKM5__00

CBS 4 News:
http://www.youtube.com/user/cellmedicine#p/u/19/mxd6t3izxtw