Cells4Life Stem Cells - A Clinical Update 2009

Stem cells -a clinical update

Prepared for:Healthcare and Medical Professionals

Prepared by:

Rebecca Rutter BSc. Hons | Operations Manager

Richard M Donavan BSc (Hons) MSc LIBMS | Laboratory Manager

2009www.cells4life.com

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Cells4-A clinical update cover:Layout 1 22/5/09 14:49 Page 1

Stem cells - a clinical update

IndexPage

3 Overview.

4 A Brief History of Stem Cells.

5 What is a Stem Cell?

7 Umbilicle Cord Blood (UCB) Stem Cells and Regenerative Medicine.

8 UCB, Cancer and Leukaemia.UCB, Cardiac Research and Therapeutics.

9 UCB, Huntington’s, Alzheimer’s and Parkinson’s.UCB, Stroke and other Neurological Injuries and Conditions.

10 UCB and Haematological Diseases and Disorders.

11 UCB, Bone and Osteogenic Diseases and Conditions.UCB, Ocular and Diseases and Conditions of the Eyes.UCB and Liver Disease.UCB and Autoimmune Diseases.

12 General Overview.

13 Diseases and Conditions in Focus.

14 The Law and Stem Cells (United Kingdom)

14 History.

15 Third Party Agreements.What you should do.

16 Overcoming Current Limitaions.

17 Cells4Life - Setting an Example.

18 The Future.

19 Glossary.

20 References.


Overview

‘Stem Cells – A Clinical Update 2009’ is a working document written andproduced by the Medical Scientists working at Cells4Life. It is intended toprovide the reader with an overview of the most up-to-date legislation andthe clinical and therapeutic applications of umbilical cord blood (UCB).

All the technical staff working at Cells4Life are dedicated UCB stem cellspecialists and as the leading private UCB storage company in the UK, we areacutely aware of the questions and queries posed to us by patients,healthcare professionals and the public. This document should be able toprovide the answers.

Ultimately, the aim of this document is present information on:

• UCB as a valid source of stem cells

• The use and limitations of stem cells

• The role of UCB in regenerative medicine

• Areas of research and clinical trials

• Up-to-date legislation

• Overcoming problems

• The futureAt Cells4Life we are well aware that the process of deciding to store a child’s UCB for future potentialtherapeutic use can be a confusing one. Factors such as deciding on whether to store and/or donate to a publicor private bank, which company to use and cost can all influence ones decision. With the help and guidance ofknowledgeable and impartial healthcare professionals the process can in fact, be one of the easiest and bestdecisions you’ll ever make.

Stem cell research is one of the fastest moving fields in medicine and the number of disciplines turning to stemcells as a source of treatment is rapidly increasing. At the 3rd World Congress of Regenerative MedicineConference 2007 held in Leipzig, Germany it was noted by the Chair of the European Society of OrganTransplant (ESOT) that stem cells were the realistic option for a known field where demand far outstrips supply.

All the information set forth in this document comes from peer-reviewed academic and scientific press (journals)and reputable sources, all of which are publically available for review.


A Brief History of Stem CellsIn the early years of the twentieth century European scientists discovered that all the various types of blood cells inthe body (red blood cells, white blood cells etc) all began life as one particular type of ‘stem cell’ beforedifferentiating and becoming a specialised type of cell. These stem cells are now known as ‘haemopoietic stemcells’ (‘haemopoietic’ meaning ‘pertaining to the blood’). However, it wasn’t until 1963 that the first quantitativedescriptions of the self-renewing activities of transplanted mouse bone marrow (BM) stem cells were firstdocumented. As a result of these remarkable properties, scientists realised the potential benefits of stem cells andstem cell therapy.

In the last fifty years, this realisation has materialised into countless successful stem cell based therapies for anumber of haematologic, metabolic, oncologic and genetic diseases. Outlined below is a brief timeline of significantevents in the history of stem cells.

1959 – First animals created by in-vitro fertilisation (IVF)1968 – Discovery of haemopoietic stem cells1978 – Stem cells first discovered in human umbilical cord blood1981 – First in-vitro stem cell line developed from mice1988 – Embryonic stem cell lines created from a hamster1993 – First unrelated cord blood transplant1995 – First embryonic stem cell line derived from a primate1997 – First lamb cloned from stem cells1998 – First human embryonic stem cell lines created2001 – Focus on human embryonic stem cells and umbilical cord blood stem cells2005 – Researchers in the UK develop cord blood-derived embryonic-like stem cells

Within the human body, there are various sources of haemopoietic stem cells which include umbilical cord blood,bone marrow, peripheral blood and amniotic fluid and membranes. While harvesting stem cells from the bonemarrow has long been traditional, this method is now becoming outdated as it is invasive can be very painful andfor a number of reasons create ethical, moral and racial problems for the recipient. As newer sources of stem cellshave been discovered, such as umbilical cord blood (UCB), the majority of these issues are no longer a problem.UCB is a rich source of stem cells and the collection of UCB is painless, non-invasive and simple.Furthermore, it raises no ethical or moral debate.

The first successful use of UCB stem cells was in 1988 when a child from the United States with Fanconi’s anaemia(a rare form of aplastic anaemia) was treated with their siblings UCB (Gluckman et al, 1989). The recipient of thetransplant remains alive and well today. More than twenty years later, even greater success is still being seen withUCB having been used in over 6000 transplants to date.

It is now widely recognised that UCB is the mainstay of many transplants around the world. In recent years witheven greater success, UCB transplants have come into their own as therapeutic options for a variety of diseasesand conditions. In late 2007, a three-year old girl from New York in the USA was diagnosed with acutelymphoblastic leukaemia and treated with her own UCB stem cells. The rationale for storing the sample and themethods used were virtually identical to that of Cells4Life. After 20 months, the girl is in complete remission of thedisease and is doing well (Hayani et al, 2007). More recently still, a case report published in the Chinese MedicalJournal reports the case of a 15-month old girl diagnosed with malignant infantile osteoporosis (MIOP) who wastreated with an allogenic UCB transplant and is now doing extremely well with the disease in total remission after 4months of therapy (Tang-Her et al, 2008).

Due to the undeniable life-saving potential of stem cells, stem cell research is one of the biggest areas of modernmedical science. Currently, over 2000 articles per year based on stem cell research are published in reputablescientific journals. With breakthroughs being announced on an almost daily basis, stem cell therapy is becomingcommonplace. The possibilities for stem cell research are truly endless, and yet unpredictable. If scientists canmaster the complex biochemistry behind stem cell development, stem cell technology could be used to producereplacement organs and to repair defective tissues/organs that have been damaged or destroyed by many of themost devastating diseases and disabilities.


What is a Stem Cell?As scientists discover more and more about stem cells, the exact definition of a stem cell can be a little confusing,and every stem cell scientist will probably give you a different answer were you to ask them!

Essentially, a stem cell is a type of cell in the body which possess the following traits:

• The most primitive cell type

• They are found in most, if not all, multi-cellular organisms

• Capable of self-renewal through mitosis

• They are undifferentiated

• Can give rise to specialised cell types

Stem cells have two important characteristics that differentiate them from every other cell type in the body – firstly,they are unspecialised cells that can renew themselves over long periods of time via a process called mitosis. Onefundamental property is that they have no tissue-specific structures that allow them to perform specific functions.Secondly, under certain physiological conditions, stem cells can be induced to become other cell types withspeacialised functions such as heart muscle cells or insulin-producing cells of the pancreas. When a cell replicatesitself many times it is said to ‘proliferate’. A population of stem cells that proliferates for many months in alaboratory can yield millions of cells. If the resulting cells remain unspecialised, the cells are said to be capable oflong-term renewal.

Categorisation of stem cells is in fact rather complex so for simplicity, stem cells can be thought of as being in threedifferent groups, all capable of doing something ‘different’.

Pluripotent stem cell (PSC)

These are the true stem cells, with the potential to make any of the differentiated cells in the body. Three types ofPSC have been found - embryonic stem cell (ESC), embryonic germ cell (EGC) and embryonic carcinoma cells(ECC).

Totipotent stem cell (TSC)

This type of stem cell is called totipotent (‘toti’ being Latin for ‘whole’ or ‘total’) as it has the potential to becomeANY other type of cell in the body, including those that make up the cells of the extra-embryonic membranes (i.e.the placenta)

Multipotent stem cell (MSC)

These are also true stem cells but unlike the types of stem cells, can only differentiate into a limited number ofdifferent cell types.

The availability of cord blood as an alternative to bone marrow as a source of haematopoietic stem cells (HSC) forboth autologous and allogenic transplantation has a number of potential advantages for both adults and children inclinical practice. These advantages include:


• Faster availability – patients on average receive cord blood transplants (CBT) earlier than those receiving

conventional BM grafts

• Extension of the donor pool – CBT will tolerate a mismatch of tissue types between donor and recipient

greater than is acceptable with BM or peripheral blood

• Because of the ethnic diversity of cord blood donors, there is a higher frequency of non-Caucasian HLA

haplotypes available compared with BM registries

• Lower incidence and severity of graft versus host disease (GvHD)

• Lower incidence of viral transmission, particularly cytomegalovirus (CMV) and Epstein-Barr virus (EBV)

• Lack of donor attrition – BM donors may change their mind or become unavailable over time

Figure 1 – Differentiation of Stem Cells in Haemopoietic Cells

Image copyright of LifeEthics.org (2008)


Umbilical Cord Blood (UCB) Stem Cellsand Regenerative MedicineStem cell biology and regenerative medicine represent a new frontier for the scientists and doctors at the forefrontof modern healthcare. In the last decade, attempts have been made with great success at treating a wide range ofthe most common diseases and conditions affecting human health.

Clinical trials using autologous and non-autologous stem cells from a variety of sources are increasing. Variousmedia outlets (broadsheet newspapers, TV, radio etc) report almost daily on new scientific advancements usingstem cells as a treatment (or potential treatment) for many diseases. There is wealth of published literaturereferencing the ongoing science and research of using UCB and regenerative medicine.

Outlined below are just some of the key classes of diseases where UCB stem cells (and other types of stem cells)have been used in therapy as well as some current areas of research.

Class of Disease Example

• Metabolic Diabetes, glycogen storage disease (GSD),phenylketonuria, liver disease, Tay-Sachs disease,Hunter’s Syndrome

• Oncologic Various leukaemias, lymphomas, cancers

• Immunologic Multiple sclerosis (MS), Crohn’s disease, lupus,rheumatoid arthritis (RA), chronic granulomatousdisease

• Genetic Sickle cell anaemia, thalassaemia, Fanconi’s anaemia

Extensive research in the area of regenerative medicine is focused on the development of cells, tissues and organsfor the purpose of restoring function through transplantation. The general belief is that replacement, repair orrestoration of normal function is best accomplished by cells, tissues or organs that can perform the appropriatephysiological/metabolic duties better than any mechanical device, recombinant protein or therapeutic or chemicalcompound. Several strategies are currently being investigated and include cell therapies derived from autologousprimary cell isolates, cell therapies derived from established cell lines, stem cells derived from a variety of sourcesincluding bone marrow, mesenchymal stem cells, cord bloodcells, embryonic stem cells as well as cells, tissues and organsfrom a variety of genetically modified animals (Fodor, 2003).

Figure 2 – Focus of UCB and RegenerativeMedicine

Image Copyright of Japan Tissue Engineering Co. Ltd (J-TEC)


UCB, Cancer and LeukaemiaThe outcomes of various clinical trials using stem cells in cancer therapy have cited results where fewer infectionshave been found, accelerated reconstitution of cellular make-up, statistically significant reduction in GvHD andfaster haematological recovery (Sagar et al, 2006).

The results of two studies published in the New England Journal of Medicine show that UCB is an acceptablealternative of stem cells where a suitable bone marrow donor is unavailable. The findings, reported by Europeanand US research groups offer promising alternative to thousands of leukaemia patients in need of treatment3.

At the 6th Annual International Umbilical Cord Blood Transplantation Symposium held in Los Angeles, AssistantProfessor Kent Christopherson II PhD, stated that his research as well as others in the same field, had great hope instem cell therapeutics showing positive results.

In a paper presented by Kazumi (2003), the author highlights the use of UCB stem cells to successfully treat ayoung girl with myelodysplastic syndrome (‘pre-leukaemia’) associated with Behçet disease.

Studies conducted by researchers at the University of Minnesota in the US have demonstrated the safety andefficacy of UCB transplantations after non-myeloablative therapy. Moreover, the team’s data support theconclusion that older patients with high-risk haematological diseases can now be offered UCB treatment with non-myeloablative conditioning as a potential curative treatment option (Brunstein et al, 2007).

Other noted publications and research:

Patient remains in remission 33 months after cord blood transplant (CBT). CBT thus could be an appropriatesource for patients with advanced NK/T lymphoma who have no HLA-matched donors’ (Yokoyama et al, 2007).

The use of cancer stem cells has opened new areas of research in carcinogenesis and future treatment options’(Sagar et al, 2007).

UCB, Cardiac Research and TherapeuticsResearchers at Imperial College, London, are perfecting a technique to rebuild a heart severely damaged andscarred by disease or cardiac arrest. This could eventually lead to the end of heart transplants in the UK whereheart related conditions kill 238,000 individuals every year1.

A study by Schmidt et al (2004) showed that UCB endothelial cells demonstrated excellent growth potential fortissue-engineered vascular grafts that could replace human heart defects. The findings offer a compelling reason whyparents with a child diagnosed intrauterinely with congenital defects should consider preserving their childs cord blood sinceit may offer a treatment option in the future.

Research presented at the American Heart Associations (AHA) scientific sessions in 2008 showed that stem cellsharvested from UCB can be grown ex-vivo to produce the foundations of new heart valves. Research lead andcardiac surgeon Ralf Sodian M.D said at the conference, ‘tissue engineering provides the prospect of an ideal heartvalve substitute that lasts throughout the patients lifetime and has the potential to grow with the recipient andchange shape as needed2.’

Clinical trials outlined in a paper by Dimmeler et al (2005) show how transplantation of stem cells (from varioussources) in cardiac defects have shown significant improvement in function. The author cites that ‘recentexperimental studies early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as anachievable therapeutic target.’

In a summary of clinical trials outlined by Renault and Losordo (2008), the authors highlight some of the researchinto cardiac repair (angiogenesis) using a variety of stem cells. Whilst the authors rightly point out some of the


concerns that go in hand with new therapies, there is clear evidence that the use of stem cells has to date, provedeffective and safe.

Further research summaries:

Heart Repair and Stem Cells (van Laake et al, 2006).

Umbilical cord blood derived stem cell therapies designed for regenerative treatments of ischemic diseases ofhuman myocardium (Bonanno et al, 2007).

Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesisin myocardial infarction (Hu et al, 2006).

Cardiac troponin T [in cord blood] may be a useful marker for myocardial damage in neonates’ (Clark et al, 2001).

Unchain my heart (paper) – The scientific foundations of cardiac repair’ (Dimmeler et al, 2005).

UCB, Huntington’s, Alzheimer’s and Parkinson’sIn 1995 it was suggested that immature stem cells existing in umbilical cord blood (UCB) might have anameliorating effect on neurological diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) andParkinson’s disease. Since this time, animal models have shown that UCB mononuclear cells significantly delay theonset of these conditions. Furthermore, it has since been shown that this effect was greater than when using BMstem cells (Ende et al, 2002).

In pre-clinical studies published in the March 2008 issue of Stem Cells and Development show that stem cellsderived from UCB are showing early potential in fighting Alzheimer’s disease5.

Cell therapy for Huntington’s disease (paper)’ (Dunnett et al, 2004).

In-vivo induced pluripotent stem cell or neural cells through ‘forced gene expression’ can be used to repairdamaged brain areas or treat degenerative diseases’ (Yuan et al, 2008).

The promise of stem cells in Parkinson’s disease’ (Langston, 2005).

The successful generation of an unlimited supply of dopamine neurons will make neurotransmitter transplantationwidely available for patients with Parkinson’s disease. ESC are opening an exciting era in human therapeutics’(Freed, 2002).

Cell replacement therapy: helping the brain to repair itself (paper)’ (Lindvall et al, 2004).

Widespread effective clinical applications generated by hESC technology will become mainstream over the nextdecade’ (Ormerod et al, 2006).

Activating stem cells may treat Alzheimer’s’ (paper) (Tanne, 2005).

UCB, Stroke and other Neurological Injuriesand ConditionsClinical trials have shown that delivery of circulating CD34+ cells from human UCB can produce functionalrecovery in an animal stroke model with concurrent angiogenesis and neurogenesis leading to some restoration ofcortical tissue (Peterson, 2004).


A leading paper published by Ichim et al (2007) highlights the growing success of UCB stem cells in the treatmentof autism and associated disorders as well as the stimulation of angiogenesis in various models of ischemia.

Research at the University of Illinois College of Medicine headed by Dr Dasari show that human UCB stem cellshold great promise for therapeutic repair after spinal cord injury. The results of this ongoing study show that UCBstem cells are beneficial in reversing the behavioural effects of spinal cord injury (Dasari et al, 2007).

Clinical research summarised by Walker et al (2009) showed that various stem cell therapies for traumatic braininjury vastly improved the outcomes of subjects up to 20%.

Further research summaries:

Umbilical cord blood-derived mesenchymal stem cells were able to transdifferentiate into bone and 2 types ofneuronal cells in-vitro (Park et al, 2006).

New evidence suggests that delivery of circulating CD34+ human umbilical cord blood cells can produce functionalrecovery in an animal stroke model (Peterson, 2004).

Cell therapy for Huntington’s disease (paper) (Dunnett et al, 2004).

In-vivo induced pluripotent stem cell or neural cells through ‘forced gene expression’ can be used to repair damagedbrain areas or treat degenerative diseases’ (Yuan et al, 2008).

The promise of stem cells in Parkinson’s disease (Langston, 2005).

The successful generation of an unlimited supply of dopamine neurons will make neurotransmitter transplantationwidely available for patients with Parkinson’s disease. ESC are opening an exciting era in human therapeutics (Freed,2002).

Cell replacement therapy: helping the brain to repair itself (paper) (Lindvall et al, 2004).

Widespread effective clinical applications generated by hESC technology will become mainstream over the nextdecade (Ormerod et al, 2006).

Activating stem cells may treat Alzheimer’s’ (paper) (Tanne, 2005).

Umbilical cord blood-derived mesenchymal stem cells were able to transdifferentiate into bone and 2 types ofneuronal cells in vitro’ (Park et al, 2006).

New evidence suggests that delivery of circulating CD34+ human umbilical cord blood cells can produce functionalrecovery in an animal stroke model’ (Peterson, 2004).

hUCB (human umbilical cord blood) facilitate functional recovery after moderate spinal cord injury and may proveto be a useful therapeutic strategy to repair the injured spinal cord’ (Dasari et al, 2007).

Results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbsof rats after spinal cord injury’ (Dasari et al, 2008).

UCB and Haematological Diseases and DisordersAt the first International Symposium on Stem Cell Research and Therapy (2006) scientists from the world overprovided an optimistic approach in the use of UCB stem cells in the treatment of haematological malignanciespreviously thought to be incurable citing UCB-derived stem cells the only viable option in a number of linkeddisorders.


The successful use of UCB stem cells to treat a wide variety of haematological has been demonstrated. A study byYoung et al (2006) highlighted the successful use of UCB to treat severe aplastic anaemia with its low risk of GvHD.

Studies by Kim at al (2006) conducted at the College of Medicine, Korea, found that UCB stem cells transplantedinto patients with Buerger’s disease and ischemic limb disease had significant improvement in deterioration of limbpain, improved angiogenesis and improved peripheral circulation.

UCB, Bone and Osteogenic Diseases and ConditionsOngoing research by Tomlinson et al (2008) compares the osteogenesis of human embryonic stem cells, UCB-derived mesenchymal stem cells and BM-derived stem cells with promising results. The researchers have found thatunder osteogenic conditions, all three sources of stem cells can differentiate to form osteoblast like cells.

Highly successful treatment of malignant infantile osteoporosis (MIOP) using UCB stem cells was outlined by Jainget al (2006). The recipient used donor UCB that was a 2-loci HLA mismatch. This case suggests that in the event ofunmatched donor availability, UCB stem cells are a feasible option for therapy.

Other papers of note:

Human umbilical cord blood–derived mesenchymal stem cells have been found to have significantly higherosteogenic potential’ (Kim et al, 2008).

Successful unrelated cord blood transplantation in a girl with malignant infantile osteoporosis ( Jaing et al, 2008).

UCB, Ocular and Diseases and Conditions of the EyesAt the Annual Meeting of the Association for Research in Vision and Ophthalmology held in Florida in 2008,researchers lead by Professor Whei-Yang Kao, announced that stem cells may be used to cure genetic diseases ofthe eye4.

UCB and Liver DiseaseUmbilical cord blood cells, fetal liver progenitor cells, adult liver progenitor cells and mature hepatocytes have allbeen reported to be capable of self-renewal, giving rise to daughter hepatocytes both in vivo and in vitro’ (Bae,2008).

Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens’(Brezillion et al, 2008).

UCB and Autoimmune DiseasesStem cell based therapy is a well established approach to treat a wide variety of autoimmune diseases (AD). Dazziet al (2007) highlights the ongoing research that in the last 10 years has seen significant improvement in thesuccessful use of haemopoietic stem cells for otherwise untreatable forms of AD.

Researchers at the University of Illinois, Chicago, have found that by using UCB stem cells in the treatment of type Idiabetes there was marked elimination of hyperglycaemia with restored islet function and architecture. The findingsof this study outline a new strategy for the prevention and treatment of diabetes and other autoimmune diseases(Zhao et al, 2009).

Autologous umbilical cord blood infusion for type I diabetes (Haller et al, 2008).


Human umbilical cord blood mesenchymal stem cells can differentiate into islet-like cells in vitro and extracellularmatrix (ECM) gel plays an important role in pancreatic endocrine cell maturation and formation of three-dimensional structures’ (Gao et al, 2008).

Mesenchymal stem cells: Biology and clinical potential in type I diabetes therapy’ (Liu et al, 2008).

General OverviewUCB is a valuable source of stem cells for transplantation in the treatment of a variety of haematological,oncologic, immunologic, and metabolic disorders. In the last few years an increasing number of patients havereceived cord blood transplants with great success (Tanaka et al, 2006). Various studies have shown, and currenttherapeutic strategies demand, that stem cells are cryopreserved for virtually all autologous, as well as manyallogenic, transplants (Berz et al, 2007).

By far, the majority of UCB transplants have occurred in the paediatric setting. This reflects a perspective that thenumber of stem cells harvested from a typical cord blood collection is limited to infants and young children (Rogerset al, 2001). However, this said, methodologies and techniques to increase the number of viable stem cells andprogenitor cells from a single sample are rapidly becoming commonplace. The In-vitro amplification of stem cellswill undoubtedly aid in the applicability and success rate of such treatments although optimum collection,processing and storage is of course paramount.

Haemopoietic stem cell transplantation is now regarded as a safe and acceptable therapy for many cancers andinherited disorders that originate or manifest as primary abnormalities of the blood or bone marrow (BM). Atransplant of this type can use stem cells collected from the patient (autologous) or from a suitably matched donor(allogenic). Donor-recipient compatibility is determined by matching specific Human Leukocyte Antigens (HLA).The degree of homology, i.e. how well the two tissues match, will determine how well the transplant will work.Within families, siblings have a 1 in 4 chance of good HLA homology as each child inherits one of each of the twomaternal and paternal haplotypes.

Some of the problems encountered with bone marrow (BM) transplants involve finding a suitable match in time forthe transplant to happen. Despite there being nearly 10 million registered donors worldwide, only 50% of whitepatients will find a suitable match (Confer, 1997). In ethnic minorities, this number is much lower, reflecting thelower number of ethnic minorities registering themselves as donors. Clearly, there is a need for stem cells and UCBis prominent in both the research and clinical setting as a therapeutic source of these amazing cells.

Figure 3 – In-vitro Differentiation of Stem Cells

Image Copyright of ProQuest, 2008


Diseases and Conditions in FocusSince the advent of stem cell-based therapies to treat a wide variety of diseases and conditions, scientific andmedical research has started to focus on the more destructive ailments affecting human health. Below is a list ofsome of the conditions on which research using UCB stem cells if focused.

Type of Disease Examples

Leukaemias, lymphomas and Acute lymphocytic leukaemia (ALL),other bloodcancers acute myelogenous leukaemia (AML),

Hodgkin’s lymphoma, adultT-cell leukaemia, multiple myeloma

Other cancers Renal cell carcinoma, neuroblastoma, small-cell lungcancer, brain tumors

Bone marrow disorders Severe aplastic anaemia, Fanconi anaemia, BlackfanDiamond anaemia, congential cytopenia

Haemoglobulinopathies Beta thalassaemia major, sickle cell disease

Myeloproliferative disorders Amyloidosis, acute myelofibrosis,chronic myelomonocytic leukaemia

Inherited metabolic disorders Hurler’s syndrome, Hunter’s syndrome, Krabbesdisease, Lesch-Nyhan syndrome, Tay-Sachsdisease, mucolipidosis

Inherited immune disorders Chronic granulomatous disease, congenitalneutropenia, SCID, X-linked lymphoproliferativedisorder

As well as the diseases and conditions listed above (which is no way exhaustive) increasing emphasis is beingfocused on the likes of heart related diseases, brain injury and spinal repair, diabetes and cerebral palsy. Some ofthe most widely investigated illnesses using stem cells as treatment reflect some of the most common causes ofmorbidity and mortality of our time. These include a variety of cancers, neurodegenerative disease, autoimmuneand metabolic disorders. Figure 4 summarises which types of diseases and conditions are focused on.

Figure 4 – Focus of stem cell research as of 2008

Image copyright of New York State Stem Cell Science (NYSTEM). 2008.


As science progresses (as it always does), there is rapidly growing acknowledgement throughout the medical,scientific and academic world that UCB stem cells are a real, acceptable source of therapy for numerous diseases.

A leading paper published in the acclaimed Journal of Translational Medicine written by Riordan et al in 2007summarised the current opinion of the use of UCB stem cells citing the outcomes of treatment for a number ofdiseases treated using UCB stem cells.

Duchenne muscular dystrophy ‘‘…physical examination revealed obviousimprovement in walking, turning the body over,and standing up…’

Refractory anaemia ‘…all patients are alive and free of disease atbetween 17 and 39 months after cord bloodadministration…’

Spinal cord injury ‘…improved sensory perception andmovement…regeneration of the spinal cord atthe injured site…’

Non-healing wounds ‘…accelerated healing…’

Malignant infantile osteoporosis ‘…normalisation of spine bone mineral density…’

Rothmund-Thompson Syndrome ‘…complete immune reconstitution…’

Behcet’s disease ‘…Twenty-three months after CBT (cord bloodtransplant) the patient is doing well and has nosigns or symptoms of Behcet’s disease…’

The Law and Stem Cells (United Kingdom)2008 saw a radical change in the regulation of procurement of cord blood. Given the impact this has made notonly to donations to public banks but also to private banks this section is designed to provide a clear understandingof the current legislation and allow healthcare professionals to understand exactly what is needed in order toprocure cord blood in accordance with the law. The guidance referred to in this section is taken from the HumanTissue Authority (HTA), the responsible body for enforcement of this legislation in the United Kingdom.

…It is imperative to understand that failure to ensure that cord blood procurement is achievedunder the auspices of a Human Tissue Authority license (either directly on a licensed premisesor by way of a Third Party Agreement) is a breach of the legislation and is therefore anoffence under the Human Tissue Act Quality and Safety Regulations 2007.

HistorySince 2002 private banking of a childs’ umbilical cord blood (UCB) has been possible in the United Kingdom. Thisoption has been widely available in the USA for some preceding 10 years, and is rapidly becoming “the norm”. Inthe UK, in response to this novel patient demand, the Royal College of Midwives (RCM) published a PositionStatement regarding commercial collection of UCB in December 2002. Subsequently, the Royal College ofObstetrics and Gynecology (RCOG) published an Opinion Paper on this matter June 2006. Both these papersnoted that patients were increasingly likely to ask for this, and highlighted the important practical issues of liabilitycover, prioritisation of care and resource availability.

Prior to 2002 the options to bank cord blood were limited to USA based companies who shipped the blood back


to the USA for processing and storage. In 2002 the first UK based cord blood bank was opened (Cells4Life Ltd)and was subsequently followed by many more. At present there are four UK based established private cord bloodbanks, and one recent addition, as well as numerous US and European based operations which have arisen.

2004 saw the introduction of the Human Tissue Act (HT Act), transposed from the European Tissue and CellDirective 2004 (EUTCD) regulated by the HTA. On 30 April 2008 the HTA announced that the procurement ofumbilical cord blood was to be regulated in the same manner as other organ donations, and would thereforerequire a license.

The options for licensing compliance are:

1. A license (present suggested fee for 2009 is £6000) for the institution where cord blood is procured e.g. hospitalmaternity unit. Clearly this is costly and does not cover home birth scenarios

2. A third party agreement with a licensed institution either with an individual or with another institution whoprocure cord blood on behalf of the licensed entity

Third Party AgreementsHuman umbilical cord blood is taken with the express purpose of being used in a therapeutic treatment at somepoint in the future. This is no different to any other organ or tissue type, with the exception that the use may bemany years in the future, and for diseases which are not currently treatable. Procurement must therefore betraceable and occur in a suitable manner and place.

Third party agreements (TPA) are specifically provided for in the legislation. It is a formal agreement, legally bindingunder the HT Act 2004, which specifically makes each party aware of their duties and responsibilities. It includesfor instance an obligation to ensure that the person documents any event which may impact the sample. Anexample would be the mother suffered a haemorrhage which resulted in her receipting a blood transfusion so thematernal blood sample provided would be useless in terms of disease marker testing.

It is highly likely that healthcare professionals who work within the NHS are not covered by the NHS insurance ifthe procurement is taken for any other purpose than NHS use. However there are exceptions where the NHSTrusts have entered into commercial agreements for procurement. It is therefore necessary for each healthcareprofessional to ensure they are fully aware of the current policy of the hospital they are working for.

What you should do

• Ascertain if the organisation you are working for permits cord blood procurement

• Ascertain if there is either a license OR a third party agreement in place between you, your employer

and the company who is supplying the client service

• Ensure you are trained in the process of procurement

• Ensure any documentation is completed, including where relevant details of the birth etc which may

affect the sample

Should you be asked to procure blood and you are not sure if there is a TPA in place, please make contact with theorganisation in advance. Should blood be procured without a TPA this may adversely affect the storage potential ofthe sample.


Overcoming Current LimitationsThe process of procuring and storing UCB for future therapeutic use is a relatively new concept in medicine andbecause of this there are many problems to overcome in the near future. Various studies which have includeddoctors, midwives, the public and other various interested parties have shown that many of the problems faced atthe moment in cord blood banking stem from the following (Fernandez et al, 2003):

• Lack of public knowledge• Little of no understanding of regenerative medicine• Personal opinions of healthcare professionals (midwives etc)• Lack of utilisation by clinicians• Ongoing debate ‘is there a need for cord blood banking?’• Cost of private banking• Accessibility of cord blood banking related services• Opponents of cord blood banking making exaggerated, erroneous and misleading statements for their ownbenefit

Overcoming current limitations will take time. Lack of knowledge and misunderstanding exists for a number ofreasons. As with all new advances in science and medicine, public perception can be difficult to overcome. Termssuch as ‘embryonic stem cell research’ make some people scowl without having any idea what it really is. In early2008 when the subject of stem cell research was bought up in parliament, MPs were asked to vote on whether isshould be allowed or not. In a straw poll conducted after voting it was established that the vast majority of MPsdidn’t even have a clue what a stem cell even was. So much misunderstanding comes from individuals who havevery little knowledge of what stem cells are and how they tie in with the concept and reality of regenerativemedicine. Moreover, it can be difficult to get healthcare professionals to accept new, improved or wholly differentstandards and/or developments in their specialist fields.Experience has also shown that the personal opinions of some ‘healthcare professionals’ can skew individualdecisions. An ongoing example is that of an expectant mother whose first point of call for cord blood banking maywell be in conversation with her midwife. If the midwife, and for no legitimate reason disagrees with, or part orwhole of the process of cord blood banking, then this generally influences the mothers’ opinion in a negativemanner.

As with all new concepts in science and medicine, there will always be outright opponents. The fact of the matter iscord blood banking is undertaken entirely of free will and no-one in the industry is forcing the issue. There is awealth of published scientific literature supporting and proving the benefits of UCB banking and subsequent use.That is a FACT. Most opponents of private cord blood banking have motives that aren’t specifically aimed at cordblood banking, it may be that the concept or business ‘gets in the way’.

There is no doubt that we now live in society where the public have such high expectations of scientists anddoctors, it is essentially demanded that we find cures and treatments for virtually every illness, disease andcondition that affects us. This cannot be done without support and the right approach. Hopefully, with moreknowledge, more questions being asked and more interest, the public and healthcare professionals alike will acceptthat regenerative medicine and the use of UCB as a source of stem cells is here to stay and will soon becomecommonplace.

The problems associated with UCB banking don’t just stem from perception. There are plenty of scientificlimitations yet to overcome. Several innovative strategies are aimed at increasing the cell dose are being explored(see below).


Transfusion of a source of stem cells i.e. UCB stem cells, usually occurs via standard blood transfusion techniques. Itresults in recruitment and differentiation of the transplanted cells as well as recruitment of host cells to the effectedarea. This has been demonstrated in prominent studies involving retinal surgery, diabetes and cerebral palsy.

Strategies to overcome limitations of low cell dose in UCB transplants:

CONCEPT SOLUTION

Using a bridging population Double unit UCB transplantduring engraftment period

Using host cells to bridge Non-myeloablative or reduced sensitivityengraftment conditioning

Improve homing Direct injection of UCB cells to target area

Increase the number of Ex-vivo expansion of stem cellsstem cells

Therapeutic cell dose has been hotly debated, with the current figure being approximately 20 millions cells per kgof body weight. Clinical phase I trials using ex-vivo expanded cells are now underway.

Cells4Life – Setting an ExampleAt Cells4Life Ltd we are, and always have been, committed to setting an example in the industry of cord bloodbanking. At our own established state-of-the-art laboratory based on the University of Sussex, Brighton, we arenow the UKs foremost UCB bank.

One of the first things that set us aside from other UCB banks in the UK is that as a company, we own and operateour own laboratory with full processing and storage facilities. The majority of other UCB banks use contractedlaboratories that do not specialise in UCB processing and storage. Furthermore, by using contracted laboratories,you simply do not get the staff with the specialist knowledge and skills needed to deal with UCB banking. AtCells4Life, all our Medical Scientists, Medical Doctors and Laboratory Technicians are dedicated stem cell specialists.

Cells4Life is the only UCB bank in the UK to store whole blood. There is no scientific evidence supporting the useof separated UCB over whole UCB in autologous (or allogenic) transplants. The only benefit of separating wholeUCB into its component parts is that of physical space-saving and companies that separate UCB only do so to savemoney. However, this saving cost is never passed on to the customer. At Cells4Life, we store the whole blood,regardless of volume, at no extra charge.

Figure 5 – Cutting of the umbilical cord and procurement of cord blood


At Cells4Life we strive to stay ahead of the game. We have a vast medical library of journals and articles fromsome of the leading and most well respected institutions in the field which is constantly being updated. Our libraryof resources includes the Royal College of Obstetrics and Gynecology (RGOG), The Lancet, The New EnglandJournal of Medicine, Transfusion, Bone Marrow Transplant, British Journal of Midwifery, British Medical Journal andStem Cells to name a few.

We are also one of the few companies in our field to have dedicated Medical Doctors and Medical Scientists whospecialise in stem cells and transplantation who work only for Cells4Life. Staff training and knowledge is of utmostimportance to Cells4Life. Our staff members belong to a variety of government, academic and medical institutionsranging from the Royal College of Surgeons (RCS), The Institute of Biomedical Science (IBMS), The HealthProfessions Council (HPC) and the Institute of Biology (IB).

The FutureIt will take several years of research and clinical trials to determine the exact role ESC and non-ESC will play inregenerative medicine. At present, the mainstay of transfusions are carried out using non-ESC, especiallyautologous cells, as well being used in clinical trials as well as clinical practice.

Commercial cord blood banking at Cells4Life is an established service which offers parents the opportunity to storetheir baby’s own UCB in the long-term. Should that child or his/her siblings develop any one of a number ofmetabolic, immunologic or haematologic diseases or conditions then that saved UCB has the potential to save a life.

The future of stem cell therapy is secure. With increasing advancements being made in the field of regenerativemedicine almost daily, the potential for cures and treatments foe many more conditions and diseases is now withinreaching distance. In modern medicine, individuals now have the choice of where they want to be treated, howthey want to be treated and most importantly, they have say in it and are listened to.

UCB banking is a choice made by parents in the event that there child may become ill and where stem cells are anoption for treatment. Stem cell technology, regenerative medicine and future therapies are not miracle cures, theyare the result of years of hard work and research by dedicated scientists, doctors and patients that all contribute tothe future health of our kind. This group of people will continue to work to ensure that sick individuals have accessto the latest medical and scientific advancements.

Table 1 – Storage of Whole UCB (at Cells4Life) vs. Separated UCB

Process and/or aspect of storage

Whole UCB Separated UCB

Processing of specimen Minimal (~30 mins) –

dramatically reduces exposure to detrimental elements

Extended (many hours) – increased likelihood of

contamination and loss of stem cells

Volume of UCB Cost is the same, regardless of volume

Smaller storage space but not reflected in cost

Recovery of stem cells after thawing

Minimal loss with good recovery of progenitor cells

No scientific evidence to support increased viability

Viability of UCB Nucleated cell count, viable cell count (using advanced fluorescent flow cytometry

platform FFCP)*

Numerous unnecessary tests that do not relate to transplant

viability or potential

Microbial contamination rate Low

High due to increased exposure to detrimental

elements, increased manual handling and ambient

temperatures Transplant rate High with good success rate No greater than whole UCB

transplants Side effects of transplantation Low, mild and reversible No less so than whole UCB

*See Glossary of Terms


Glossary

Allogenic – being genetically different although belonging to the same species

Autologous – derived or transferred from the same individuals body

Blastocyst – in mammals, the early result of a fertilised egg

Bone Marrow – soft, fatty vascular tissue that fills most bone cavities and a source of red and white blood cells

Donor – a person who gives or donates

Embryonic Stem Cell (ESC) – cells obtained from the embryo in the blastocyst stage

Graft versus Host Disease (GvHD) – a reaction where the cells of a transplanted tissue immunologicallyattack the cells of the host

Haemopoietic Stem Cell (HSC) – a type of stem cell that gives rise to all the other types of blood cells

Human Leukocyte Antigen (HLA) – the major class of histocompatibility antigens in humans

Human Tissue Authority (HTA) – is the UK non-departmental body created by the Human Tissue Act 2004which regulates the removal, storage, use and disposal of human bodies and tissues

In-vitro – Latin meaning ‘within the glass’. Essentially something carried out in a laboratory

In-vivo – Latin meaning ‘within the living’. Essentially something done in a living organism

Mitosis – process of cell division in which the nucleus of the cell divides resulting in two daughter cells. Generallyconsisting of four stages – prophase, metaphase, anaphase and telophase

Regenerative Medicine – is essentially medical treatment where stem cells are used to treat and/or cure avariety of conditions and diseases

Transplant – to transfer from one body to another (allogenic transplant) or from one part of the body to adifferent place on the same body (autologous transplant)

Umbilical Cord Blood (UCB) – blood collected from the umbilical cord of a term infant. A rich source ofstem cells


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Cells4Life Stem Cells - A Clinical Update 2009