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Investors' FAQs
How
was Pluristem Life Systems, Inc. founded?
Pluristem was founded after five years of cooperative research and development
by Dr. Shai Meretzki, the Technion Israel Institute of Technology and the
Weizmann Institute of Science. The Company developed a unique technology for the
expansion of stem cells, T-cells, and other blood-related cells. At present,
Pluristem is focusing on the expansion of mesenchymal stromal cells that are
derived from the placenta that is intended to be used for treating a broad range
of complicated diseases.
What is the uniqueness of Pluristem’s technology?
Pluristem’s 3-dimensional PluriX™ bioreactor utilizes mesenchymal stromal cells
that are derived from the placenta. mesenchymal stromal cells are multipotent adult
stem cells that have strong anti-inflammatory properties and can regenerate and
repair damaged tissue. When MSCs receive appropriate biochemical and
biomechanical signals they can differentiate into various tissues such as nerve,
bone, muscle, fat, tendon, ligament, cartilage and bone marrow stroma. MSCs also
have low immunogenicity, are not rejected by the patient’s immune system and,
therefore, do not require HLA matching.
Pluristem is unique in their
approach to stem cell research in that they are using:
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A
proprietary bioreactor (PluriX™) 3D system that enables the ex vivo
expansion of MSC populations in a microenvironment resembling the architecture
of natural bone marrow.
v
The
unique micro-structure enables expansion of mesenchymal stromal cells (MSC) to very
high densities. mesenchymal stromal cells have the advantage of being
immune-privileged and immunosuppressive, which means that the patient’s immune
system is less likely to reject the transplant.
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Pluristem’s (PluriX™) 3D system does not use exogenous biologics or chemicals in
their expansion process, eliminating the risk of genetic instability and
allowing for the safer expansion of cells.
How
can Pluristem’s PLX cells be used?
PLX cells are the MSCs expanded
in Pluristem’s proprietary (PluriX™) 3D bioreactor. Pluristem believes these PLX
cells are multipotent and able to differentiate into a variety of cell types as
well as being immune-privileged to protect the recipient from immunological
reactions that often accompanies transplantation. Pluristem believes their
future products will participate in the approximate $30 billion therapeutic and
regenerative cellular market.
Pluristem’s first planned product, PLX I, targets a $2
billion market and is intended to resolve the global shortfall of matched tissue
for bone marrow transplantation (BMT) by improving the engraftment of
hematopoietic stem cells (HSCs) contained in umbilical cord blood (CB).
What are
stem cells?
Stem cells are undifferentiated “mother” cells that have the ability to develop
into any kind of cell in the human body. Dedicated non-stem cells have a
specific function (e.g. liver cells, skin cells, brain cells, etc.) and once
dedicated cells have taken on their function, in a process called
differentiation, they can't be adapted for any other function.
Stem cells, however, have not yet differentiated. Stem cells can, theoretically,
multiply and differentiate an unlimited number of times and, by doing so,
replenish any and all other cells. When a stem cell divides, each new cell has
the potential to either remain a stem cell or differentiate into another, more
dedicated type of cell with a more specialized function, such as a muscle cell,
a red blood cell, a brain cell, etc.
What are the different classes of stem cells?
There are three main classes
of stem cells: totipotent, pluripotent, and multipotent
* Totipotent stem cells have the potential to become all other types of cells in
the body. A fertilized egg is totipotent.
* Pluripotent stem cells can produce any type of cell in the body except those
needed to develop a fetus. Embryonic stem cells are produced when a newly
fertilized egg begins to divide and are pluripotent.
* Multipotent stem cells can produce only certain types of cells. Adult stem
cells are multipotent and are found in adults, infants and children. mesenchymal
stromal cells (MSCs) are also multipotent adult stem cells and are found in the
placenta as well as organs that have already developed. MSCs act as a repair and
maintenance cells dividing regularly to provide the body with specialized cells
to take the place of those that die or are otherwise lost.
What are Hematopoietic Stem Cells (HSC)?
A hematopoietic stem cell
(HSC) is an adult stem cell isolated from the bone marrow, umbilical cord or
peripheral blood that can renew itself, differentiate to a variety of
specialized blood cells such as red and white blood cells and platelets. HSCs
are exclusively required for bone marrow transplantation (BMT) and are the only
cells that can reconstitute the hematopoietic or blood system following BMT.
HSCs are now routinely used to treat patients with cancers and other disorders
of the blood and immune systems. Examples of the diseases where BMT may be of
value are the following:
Acute Leukemias
Acute Biphenotypic
Leukemia
Acute Lymphocytic Leukemia (ALL)
Acute Myelogenous Leukemia (AML)
Acute Undifferentiated Leukemia
Chronic Leukemias
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelogenous Leukemia (CML)
Juvenile Chronic Myelogenous Leukemia (JCML)
Juvenile Myelomonocytic Leukemia (JMML)
Myelodysplastic Syndromes
Amyloidosis
Chronic Myelomonocytic Leukemia (CMML)
Refractory Anemia (RA)
Refractory Anemia with Excess Blasts (RAEB)
Refractory Anemia with Excess Blasts in Transformation (RAEB-T)
Refractory Anemia with Ringed Sideroblasts (RARS)
Stem Cell Disorders
Aplastic Anemia (Severe)
Congenital Cytopenia
Dyskeratosis Congenita
Fanconi Anemia
What
are mesenchymal stromal cells
(MSCs)?
mesenchymal stromal cells (MSCs)
are multipotent adult stem cells that are derived from the placenta as well as
other functioning organs. MSCs have the ability to generate supporting cells
such as those found in cartilage, bone, muscle, tendon, ligament and fat. MSCs
have the potential to replace damaged tissues and have the potential to be
expanded then transplanted to the injured site to generate appropriate tissue
constructs.
How
are stem cells used in medicine?
Researchers are exploring two
main avenues for using stem cells to treat disease
1) Stem cells as “replacement parts”: A wide range of diseases (heart disease,
Parkinson’s, Alzheimer’s, diabetes, motor neuron disease, etc.) may be amenable
to stem cell therapy if stem cells can be directed to the appropriate place in
the body and become the appropriate cell type. For example, if stem cells could
be made to migrate to an injured spinal cord and become nerve cells, it might be
possible to cure paralysis.
2) Developing drug therapies: It is possible to make stem cells that are
genetically identical to those of a patient with a disease such as amyotrophic
lateral sclerosis. The stem cells can be made to generate the cell type that is
defective in that disease (e.g. nerve cells). By studying these cells,
researchers may be able to gain insight into what goes wrong at the molecular
level in the disease. They can also use these cells to test drugs that might
block the progression of the disease.
How is a bone marrow transplant (BMT) performed?
The BMT procedure involves three phases:
v
In the
first phase, lasting 5 to 14 days, the bone marrow recipient is prepared for
receiving the graft. Immunosuppressive and cytotoxic chemotherapy is
administered and irradiation is used to prepare the recipient to accept the
graft and to prevent graft rejection;
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In the
second phase, bone marrow is obtained from a compatible donor and intravenously
administered into the patient recipient;
v
The
third phase is a period of waiting for the bone marrow to engraft and function
normally in the recipient.
How
many BMTs are being preformed each year?
There are presently over 50,000
BMTs performed worldwide (approximately 30,000 and 20,000 in the US and rest of
the world respectively) of which 5,000 are performed on babies and children.
Only one in three patients find a compatible donor with the number of patients
that could potentially benefit from BMT is estimated to exceed 150,000.
What
are the main problems in BMT?
Research and clinical work in
the field of BMT is presently limited due to:
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The
average number of active hematopoietic stem cells (HSCs) in any given bone
marrow sample is extremely low (less than 0.5%);
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The odds
of finding a marrow donor in the general population are typically 1 in 6,000,000
(American Association of Blood Banks);
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The
difficulties the human body has in accepting BMT from donors and the ensuing
transplant rejection reactions;
v
The
patient being prone to infections and other complications following radiation
and/or chemotherapy treatments;
v
The
sorting of healthy cells from cancerous cells has not proven 100% successful.
This means that the BMT can end up replacing cancerous cells with more cancerous
cells in the case where the transplanted bone marrow is autologous or coming
from the patient recipient;
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The
complications in storing and expanding these cells in vitro without
running the risk of differentiation;
What
are some of the risks associated with BMT?
During the time required for
engraftment (approximately 2 to 4 weeks), the patient recipient is vulnerable to
infection, bleeding, severe weight loss, rejection of the graft and the graft
rejecting the recipient (termed graft-versus-host disease (GVHD)). GVHD occurs
in approximately 70% of BMT patients. If the marrow engrafts and the patient
survives the immediate post-transplant period (first 3 to 6 weeks), the patient
faces another set of complications, including GVHD and interstitial pneumonia.
Interstitial pneumonia occurs in 60% of BMT patients typically 4 to 6 weeks post
transplant. The disease progresses rapidly and is fatal in approximately 50% of
the cases. Therefore, there is currently an extremely low 6% success rate among
all patients treated. (The Cost Effectiveness of BMT Therapy and Its Policy
Implications, School of Public Health, UCLA).
What
is Graft Versus Host Disease (GVHD)?
Graft versus host disease (GVHD) is one of the most common and life threatening
side effects of a bone marrow transplant (BMT). GVHD occurs when the
transplanted hematopoietic stem cells (HSCs) from the donor’s marrow recognizes
the recipient's body as foreign and, therefore, rejects it. This reduces the
survival rate of the patient to less than 50% at two years post-transplant.
However, transplants using umbilical cord blood has a noticeable decrease in
incidence of serious GVHD.
What
is Human Leukocyte Antigens (HLA) matching?
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HLA
matching refers to the matching the donor and recipient of transplanted tissue
of six proteins called Human Leukocyte Antigens (HLA) that appear on the
surface of white blood cells and other tissues in the body. These six HLA
points, or loci, determine tissue compatibility between a patient and a donor.
Although a perfect match would be best, studies have shown that cord blood
transplants are successful even when only three of the six loci match. With cord
blood, the immune cells are less mature than those in bone marrow and,
therefore, are more likely to be able to be matched to a recipient compared to
bone marrow.
What is umbilical cord blood?
Cord blood, or umbilical cord
blood (CB), is blood that remains in the umbilical cord and placenta at the time
of birth. This blood has typically been discarded following delivery. However,
Scientists are now aware that CB is a rich source of stem cells which can be
collected, processed and cryogenically preserved for potential, future use. Stem
cells from cord blood could theoretically be used as a source of cells for
transplants to treat a number of diseases.
Are umbilical cord blood (CB) stem cells different
from other types of stem cells?
Umbilical cord blood (CB) stem cells are the "youngest," safely available stem
cells.
What are the benefits of using hematopoietic stem
cells (HSCs) from umbilical cord blood (CB)?
HSCs from CB have several
important advantages over HSCs from bone marrow:
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CB
transplant patients may have a higher survival rate, a higher quality of life
after transplant and less frequent hospitalization due to complications such as
Graft versus host disease (GVHD). This translates into the overall cost of CB
transplantation being significantly less costly than a traditional bone marrow
transplantation (BMT);
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CB
transplants have demonstrated a higher rate of engraftment, more tolerance to
HLA mismatches, reduced graft-versus-host disease (GVHD) and a rarer latent
virus infection;
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HSCs
from CB are a perfect match for the child from whom they are collected, thus
eliminating the difficult process of finding a matching donor and minimizing the
risks of rejection. HSCs from CB have at least a one-in-four chance of being an
exact cell match for a sibling;
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HSCs
from CB are easier to obtain and store than HSCs from bone marrow;
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CB
collection is a quick and painless procedure with a very low risk to the mother
and newborn. Alternatively, bone marrow harvesting is an invasive procedure and
requires general anesthesia with its inherent risks;
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CB is
available and ready for transplant whenever needed.
How
is the umbilical cord blood (CB) collected?
Umbilical cord blood (CB) is
collected from the umbilical cord immediately after the birth of the baby but
generally before the placenta has been delivered. The collection can only take
place at the time of delivery. CB is easily collected using a blood collection
bag. After CB collection the umbilical cord is clamped and cut in the same
manner as it would be for a normal delivery of the baby. There is absolutely no
pain or risk to the mother or child during the collection process since the
blood is harvested from the cord once it has been cut
How is umbilical cord blood (CB) processed?
Each umbilical cord blood (CB) sample is tested to confirm the presence or
absence of a microbiological contamination and for syphilis, hepatitis, HTLV,
HIV and CMV. CB is processed using density gradient separation process and this
technique removes the red blood cells and plasma, isolating the mononuclear
white blood cells. These cells are then treated with DMSO, a cryoprotectant, and
stored in special cryo-vials with autologous plasma and media.
How is umbilical cord blood (CB) stored?
Umbilical cord blood (CB) is
stored in special cryo-vials. The cells are prepared for cryopreservation using
autologous plasma and frozen using a technique called "controlled-rate freezing"
which is used to prepare the cells for long-term storage.
How long can umbilical cord blood (CB) be stored?
Current research suggests umbilical cord blood (CB) can be stored for
fifteen years with the same resultant composition as they did at the time of
storage. There is no evidence at present that a CB cell stored at minus 196
degrees Celsius (in liquid nitrogen) in an undisturbed manner loses either it’s
in vitro-determined viability or biological activity. Therefore, at the
current time, no expiration date is assigned to CB stored continuously under
liquid nitrogen. Additionally, as bone marrow has been stored for decades and
remained viable; there is no reason to believe that the same would not be true
of CB. (Guidelines for Collection, Processing and Storage of Cord Blood Stem
Cells; New York State Department of Health)
What is an umbilical cord blood (CB) transplant?
Prior to the 1980's almost all of the incredibly valuable material from
umbilical cord blood (CB) was merely discarded after birth. The first CB
transplant took place in France in 1988 with many subsequent successful
transplants. The hematopoietic stem cells (HSCs) derived from CB have been used
in place of bone marrow for transplantation to treat a number of diseases
including malignancies including certain leukemias, Hodgkin's disease and types
of lymphoma. They have also been used for the treatment of a variety of
anemia’s, inherited metabolic disorders and deficiencies of the immune system.
The majority of CB transplants to date has been performed in patients less than
18 years old and has been sibling or allogeneic (unrelated third party)
transplants.
What is the minimum dose of hematopoietic stem cells
(HSCs) from umbilical cord blood (CB) that is needed for engraftment?
The optimal dose of hematopoietic stem cells (HSCs) from umbilical cord blood
(CB) is approximately 20 million HSCs per kilogram (2.2 lbs) of body weight.
"Patients who received no more than 10 million nucleated cells (HSCs) per
kilogram had a 75 percent probability of death, whereas recipients of at least
30 million nucleated cells per kilogram had a 30 percent probability of death."
(Editorial by Gluckman, E. NEJM 2001; 344:1860)
What is the main problem working with umbilical cord
blood (CB)?
Because of the small volume of blood collected from umbilical cords
(approximately 100 ml or 3 oz.) the use of umbilical cord blood (CB) has
traditionally been limited to babies and children weighing less than 45 kg
(approximately 100 lb). Moreover, until Pluristem’s PluriX™ 3D bioreactor
resulting in their PLX I product, there were no existing expansion
technologies that could increase the number of HSCs obtained from CB without
causing differentiation of the cells (once the cells have differentiated, they
cannot be transplanted into the patient). Therefore, the development of a system
such as Pluristem’s could facilitate the in vivo expansion of HSCs
without differentiation. Pluristem’s PLX I will potentially enable the
use of HSCs derived from CB for transplantation into adults where sufficient
HSCs were previously unavailable.
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