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Science & Research

 

Science

Summary

Magellan believes that regenerative therapies offer significant promise in the treatment of human disease and will become an important part of the treatment algorithm. Importantly the benefits of cell based therapies is not a new concept. Hematopoietic/bone marrow stem cells have had remarkable clinical success for over 40 years and serves as an important proof of concept for stem cell technologies. The term stem cell refers to undifferentiated cells that have a self renewal capacity and mutlilineage potential such that they can differentiate into more specialized cells.  They are able to respond to environmental/local stimuli and have a complex role in regeneration and organ function. Magellan’s cell based technologies are focused on the use of purified and expanded mesenchymal stem cells.  Mesenchymal stem cells have the ability to differentiate towards bone, cartilage, muscle and fat.  Recent evidence has also indicated that given the correct environment, MSCs may also have an ability to differentiate into non mesenchymal tissue including nerves.

Mesenchymal Stem Cells

Mesenchymal stem cells were first described within the bone marrow. They display plasticity and multipotency - being able to differentiate towards osteoblasts, chondrocytes, and adipocytes. Similar cells have been shown to be present in other tissues including peripheral blood, cord blood, skeletal muscle, heart and adipose tissue. MSCs are a heterogenous population of cells that lack a specific and unique marker. They are characterized by their adherent properties and expression of several surface antigens (markers) including CD105, CD 90 and CD73 and their absence of hematopoietic (blood cell) markers CD34 and CD45. It is postulated that it is there heterogeneity that allows MSCs to respond to a wide variety of cues in their local environment and therefore carry out a number of functions. MSCs lack of a speciifc cell marker also means that they are relatively immunologically inert and therefore have potential in allogeneic (from a  donor to an unrelated recipient) `off the shelf’ use. Whilst evidence of the capacity of MSCs to differentiate along a chosen cell lineage pathway represents great promise in the area of regenerative medicine it is also postulated that their beneficial effect is achieved through an immunomodulatory mechanism.  Hence their promise in the treatment of degenerative conditions but also auto-immune mediated diseases.

Intellectual Property

Magellan has intellectual property  in respect to adult adipose (fat) derived expanded mesenchymal stem cells.  

 
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Research

Background

Magellan recognizes the enormous potential of stem cells technology in the area of regenerative medicine.  Whilst the clinical success over the last 40 years in the use of bone marrow/hematopoietic stem cells serves as an important proof of concept for stem cell-based therapies, further research into the clinical application of stem cell treatments is required.  Magellan is committed to driving the clinical research of this burgeoning technology.

Osteoarthritis is the primary focus of Magellan’s current research and commercialization projects.  Importantly osteoarthritis has been declared a National Health Priority in Australia.  It is estimated that at least 3.85 million people are affected with arthritis across the Australian community, at a cost to our economy of greater than $23.9 billion each year.  Conservative estimates suggest a 58% rise in the incidence of symptomatic OA by 2032. Current medical treatment strategies for osteoarthritis are aimed at pain reduction/symptom control rather than disease modification. These pharmacological treatments are limited and can have unwanted side effects.

Clinical Trials

Magellan is dedicated to the ethical development and clinical application of stem cell therapies. In partnership with Melbourne Stem Cell Centre Magellan is funding a number of ethics approved clinical trials - primarily in regard to the treatment of osteoarthritis.

 Magellan is - and has been - involved with several clinical trials (including a randomised controlled trial - RCT) in respect to the treatment of OA in the knee. Magellan has seen - what it considers to be – very positive clinical results from its human clinical trials - both RCT and Case Series.

Clinical Results:-

Magellan has received ‘very positive’ clinical efficacy results from its numerous registered clinical trials and case series treatments. The overall clinical efficacy of Magellan’s autologous stem cell treatments is ‘impressive’. Doctors treating patients with ‘Magellan stem cells’ for osteoarthritis are reporting that the treatments appear to be leading to a significant improvement in the clinical condition of the patients having been treated with stem cells (adipose derived mesenchymal stem cells).

Review and comparison of Magnetic Resonance Imaging (MRI) of the knee prior to and after autologous mesenchymal stem cell therapy has shown cases of cartilage repair/regeneration and stabilisation of OA. This observed structural improvement and/or stabilisation may lead to the possibility to defer (or eliminate) the need for expensive joint replacement surgery.

There have been no reports of any serious adverse events. 

Magellan has also committed to funding further research in the area of lower back pain .

 
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Stem Cells and Regenerative Medicine

The term stem cell refers to any cell which is found in a developed organism that has two properties: the ability to divide and create another cell like itself and also divide and create a cell more differentiated than itself. Stem cells have the ability for:

  1.  Self-renewal capacity
  2.  Long-term viability, and multilineage potential 

Until recently, differentiation was thought to be the primary function of regenerative cells.  However, the functions of regenerative cells are now known to be much more diverse and are implicated in a highly integrated and complex network.
 
Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem Cells are multipotent and can differentiate into tendon, ligament, bone, cartilage, cardiac, nerve, muscle, blood vessels, fat, and liver tissue (see figure below). Thus, treatment using stem cells is termed "regenerative medicine" and has many potential uses for a wide variety of diseases and injuries. Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In many adult tissues, such as bone marrow, adipose, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.
 
Unlike traditional medicine, in which one drug targets one receptor, stem cell based regenerative medicine, including Magellan therapies, can be applied in a wide variety of traumatic and developmental diseases. A significant potential application of stem cells is making cells and tissues for medical therapies. The use of  stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including and arthritis, inflammatory auto-immune disorders, multiple sclerosis,  Parkinson's disease,  spinal cord and disc  injuries, burns, heart disease, and diabetes.

Given both the clinical and ethical issues surrounding the use of embryonic stem cells, Magellan Stem Cells has been pursuing the use of adult stem cells from the stroma (i.e., mesenchymal stem cells – ‘MSCs’) in the treatment of a number of conditions. Adult stem cells are found throughout the body and are present in all of us at all ages. Adult stem cells have been used internationally for the treatment of horses and dogs for many years. Most of the work has been focused on the treatment of arthritis and musculoskeletal disorders including spinal disc disorders/degeneration as well as tendon, ligament and muscle injuries.

 
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Stem Cells

In very general terms, there are three types of stem cells – embryonic, adult and induced pluripotent stem cells. Although the potential of embryonic stem cells is very significant, many ethical and political issues accompany their use. However, scientists are now utilizing stem cells of different origins; opening up the research and treatment options for humans and pets. Differing from embryonic stem cells, adult stem cells are procured from a variety of tissues, including skin, fat (adipose) and bone marrow, among other tissues. Adult stem cells are less controversial because the samples are easily obtained and the "host" is not destroyed, as with an embryo.

Embryonic Stem Cells

Embryonic stem cells, as their name suggests, are derived from embryos. Most embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro—in an in vitro fertilization clinic—and then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body. Although the potential of embryonic stem cells  is enormous, many ethical and political issues accompany their use. Mention the term "stem cells" to family and friends, though, and you are likely to get a variety of responses and opinions. Why is this? Probably because much of the early research on these cells originated from human embryos, and there are many ethical and legal debates about the procurement and usage of these cells. However, scientists are now utilizing stem cells of different origins; opening up the research and treatment options for humans and pets. Differing from embryonic stem cells, adult stem cells are procured from a variety of tissues, including skin, fat (adipose) and bone marrow, among other tissues. Adult stem cells are less controversial because the samples are easily obtained and the "host" is not destroyed, as with an embryo.

Adult Stem Cells

An adult stem cell - which is present in us in all ages, is derived from an embryonic stem cell which we obviously all have at birth. Adult stem cells are found throughout the body after embryonic development. The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. One of the difference between embryonic and adult stem cells is that adult stem cells are already partially differentiated - meaning that once you obtain them and expand them, it is a lot easier to turn them into the specific type of tissues being targeted.
 
Adult mesenchymal (stromal) stem cells (‘MSC’) offer a potentially very large therapeutic potential in the field of regenerative medicine. In cell biology, stromal cells are connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa (endometrium), prostate, bone marrow precursor cells, and the ovary as well as the hematopoietic system and elsewhere. These are the cells that make up the support structure of biological tissues and support the parenchymal cells. Originally identified as a source of osteoprogenitor cells, MSCs differentiate into adipocytes, chondrocytes, osteoblasts, and myoblasts in vitro (Hauner et al., 1987 ; Grigoradis et al., 1988 ; Wakitani et al., 1995 ; Ferrari et al., 1998 ; Johnstone et al., 1998 ; Pittenger et al., 1999 ) and undergo differentiation in vivo (Benayahu et al., 1989 ; Bruder et al., 1998a ), making these stem cells promising candidates for mesodermal defect repair and disease management. The initial concentration of researchers was on MSC’s from the bone marrow. However, the clinical use of MSCs from the bone marrow has presented problems, including low cell number upon harvest, pain, morbidity. This has led many researchers to investigate alternate sources for MSCs.
 
Adipose tissue contains a large number of stromal stem cells. Because it is easy to obtain in large quantities, adipose tissue has been found to be an ideal source of uncultured stromal stem cells. Adipose tissue, like bone marrow, is derived from the mesenchyme and contains a supportive stroma that is easily isolated. Being abundant, accessible, and replenishable, adipose tissue is an attractive source for adult stem cells that can be isolated from the adipose tissue by collagenase digestion and differential centrifugation. Fibroblasts, immune cells, pericytes, endothelial cells, and inflammatory cells are the most common types of stromal cells. Stromal cells near the bottom of the epidermis (the very top layer of the skin) release growth factors that promote cell division. This keeps the epidermis regenerating from the bottom while the top layer of cells on the epidermis are constantly being "sloughed" off of the body.

Induced Pluripotent Cells

Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell–like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.

Differentiation

In a living animal, adult stem cells are available to divide, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. Scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside. Normal differentiation pathways of adult stem cells:


The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.
•    Hematopoietic stem cells give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, and macrophages. 
•    Mesenchymal stem cells give rise to a variety of cell types: bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and other kinds of connective tissue cells such as those in tendons. 
•    Neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes. 
•    Epithelial stem cells in the lining of the digestive tract occur in deep crypts and give rise to several cell types: absorptive cells, goblet cells, paneth cells, and enteroendocrine cells. 
•    Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and to the epidermis.

Transdifferentiation

A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process. In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification. This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta-cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby avoiding issues of histocompatibility, if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

 
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Adult Stem Cells

Research on Adult Stem Cells


The history of research on adult stem cells began about 50 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow, and can generate bone, cartilage, fat, cells that support the formation of blood, and fibrous connective tissue. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for 40 years. Scientists now have evidence that stem cells exist in the brain and the heart. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies. In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell types—astrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Sources of Adult Stem Cells

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, adipose tissue, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche").

While adult stem cells (‘ASC’s) are present in many organs and tissues, the major sources of ASCs that can be obtained from an adult human are:

  1. Bone marrow

  2. Peripheral blood, and

  3. Adipose Tissue (Fat)

  4. Umbilical Cord (Whartons Jelly).

Below is a comparison of three sources:

  • Bone marrow - About 50,000 ASCs can be harvested at any one time. These mostly become blood cells.

  • Peripheral blood - About 10,000 ASCs can be harvested at any one time. 50% of which will become blood cells and 50% will become tissue cells.

  • Adipose tissue (Fat) - About 10 to 50 million stem cells can be harvested at any one time, 5% of which will become blood cells and 95% will become tissue cells.

Scientists have been carrying out extensive research to improve our ability to manipulate stem cells so as to be able to generate specific cell types so they can be used to treat injury or disease. The initial concentration of researchers was on MSC’s from the bone marrow. ASCs from bone marrow have been successfully transplanted in sufferers of leukemia and related cancers for many years (Bone Marrow Transplantation).

However, the clinical use of MSCs from the bone marrow has presented problems, including pain, morbidity, and low cell number upon harvest. This has led many researchers to investigate alternate sources for MSCs – such as adipose tissue.

Adipose tissue, like bone marrow, is derived from the mesenchyme and contains a supportive stroma that is easily isolated. Adipose tissue represents a source of stem cells that is having far-reaching effects in a large number of fields of medicine. 

Advantages of Using Adult Stem Cells


Adult mesenchymal stem cells - including stem cells that are obtained from adipose tissue (ADMSC)  are immuno-privileged cells - ie they have the ability to be transplanted – without immune rejection.