WO2014141219A1 - Transplantation de cellules souches dérivées de sang de cordon ombilical pour le traitement d'un trouble neuronal - Google Patents

Transplantation de cellules souches dérivées de sang de cordon ombilical pour le traitement d'un trouble neuronal Download PDF

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Publication number
WO2014141219A1
WO2014141219A1 PCT/IB2014/059900 IB2014059900W WO2014141219A1 WO 2014141219 A1 WO2014141219 A1 WO 2014141219A1 IB 2014059900 W IB2014059900 W IB 2014059900W WO 2014141219 A1 WO2014141219 A1 WO 2014141219A1
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cells
composition
use according
administered
spinal cord
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PCT/IB2014/059900
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English (en)
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Brian MEHLING
Dong-chen WU
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Blue Horizon International Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a composition comprising an effective amount of umbilical cord blood derived mesenchymal stem cells (UCBMSCs) for use in treating a neural disorder in a subject in need of treatment such as a placental mammal, wherein said cells are to be administered by (i) intravenous administration (ii) intrathecal administration and/or a combination thereof.
  • the present invention also relates to a method for treating a neural disorder such as spinal cord injury (SCI) in a subject such as a placental mammal in need of treatment.
  • the methods may comprise administering to the subject a composition of an effective amount of umbilical cord blood derived mesenchymal stem cells (UCBMSCs).
  • the cells are administered by (i) intravenous route, (ii) intrathecal route and/or targeted delivery. Thereby, the neural disorder may be treated.
  • SCI spinal cord injury
  • the complex pathology of SCI may be divided into primary and secondary injury.
  • the primary injury is characteristically induced by mechanical damage and resultant hemorrhage.
  • Myriad factors contributing to secondary injury include: excitatory amino acid toxicity, oxidative damage, inflammation and autoimmune response.
  • Umbilical Cord Blood contains a rich source of hematopoietic stem and progenitor cells as well as non-hematopoietic stem cells including endothelial cells, mesenchymal stem cells (MSCs) and unrestricted somatic stem cells (USSC).
  • HSCs Human Stem Cells
  • the collection of cord blood units is easy and non-invasive for the donor.
  • the stem cells from UCB can be obtained without ethical consideration.
  • cord blood units could be stored in advance and are therefore rapidly available when needed while bone marrow has to be collected from the donor just before transplantation and there is always a risk of last minute consent refusal.
  • cells from UCB can be used directly after isolation without expansion.
  • HLA human leukocyte antigen type
  • HUCBMSCs Human umbilical cord blood derived mesenchymal stem cells
  • hUCBMSCs Human umbilical cord blood derived mesenchymal stem cells
  • Transplantation of hUCMSCs into the injured spinal cord may have the following functions: compensation for demyelination; removal of inhibition; promotion of axonal regeneration; direction of axons to appropriate targets and replacement of lost cells.
  • HLA-matched UC blood-derived multipotent stem cells were directly transplanted into the injured spinal cord site of a 37-year-old female patient suffering from spinal cord injury (SCI) in Korea (Kang et al. (2005), Cytotherapy, 7(4):368.373).
  • hUCMSCs from Wharton's jelly were also transplanted to the rat spinal cord directly into the lesion site after complete transection of the spinal cord (Yang et al (2008), PLOS ONE, 3(10): 1-11). In these rats significant improvements in locomotion were observed.
  • Certain aspects of the present invention provide methods and compositions for treating a neural disorder such as an injury to the central nervous system, including spinal cord injury (SCI), in a mammal in need of treatment.
  • a neural disorder such as an injury to the central nervous system, including spinal cord injury (SCI)
  • SCI spinal cord injury
  • the present invention relates in first embodiment a composition
  • a composition comprising an effective amount of umbilical cord blood derived mesenchymal stem cells (UCBMSCs) for a therapeutic use in treating a neural disorder such as an injury to the central nervous system, particularly spinal cord injury (SCI), in a subject in need of treatment such as a placental mammal, wherein said cells are to be administered by (i) intravenous administration such as intravenous injection or infusion, (ii) intrathecal administration such as infusion or injection, targeted delivery, and/or a combination thereof.
  • UCBMSCs umbilical cord blood derived mesenchymal stem cells
  • the present invention likewise relates in an embodiment to a method for treating a neural disorder such as an injury to the central nervous system, particularly spinal cord injury (SCI), in a subject such as a placental mammal in need of treatment comprising administering to the subject a composition comprising an effective amount of umbilical cord blood derived mesenchymal stem cells (UCBMSCs), wherein said cells are administered by (i) intravenous administration such as intravenous injection or infusion, (ii) intrathecal administration such as infusion or injection, targeted delivery, and/or a combination thereof.
  • a neural disorder such as an injury to the central nervous system, particularly spinal cord injury (SCI)
  • SCI spinal cord injury
  • UCBMSCs umbilical cord blood derived mesenchymal stem cells
  • the therapeutic uses or methods may involve administering the compositions or cells to the subject with or without culturing and/or expanding and/or preserving the cells in vitro after isolation.
  • the cells may not be cultured in vitro.
  • the cells may not be incubated in any cell culture medium with nutrients for cell growth and maintenance.
  • the cells may be present in a saline-only medium or a pharmaceutically suitable carrier.
  • the cells may directly be used for transplantation or the treatment of the subject.
  • the cells may not grow or expand after isolation or before administration.
  • a neural disorder may be any disorder of the body's nervous system. They may be assessed by neurological examination, and studied and treated within the specialties of neurology and clinical neuropsychology.
  • Non-limiting examples of the neural disorders that may be prevented or treated in the certain aspects of the invention may include or exclude one or more of:
  • brain disorders such as brain damage according to cerebral lobe (see also 'lower' (1 ) brain areas such as basal ganglia, cerebellum, brainstem): including frontal lobe damage; parietal lobe damage; temporal lobe damage; or occipital lobe damage; (2) brain dysfunction such as aphasia (language), dysarthria (speech), apraxia (patterns or sequences of movements), agnosia (identifying things/people), amnesia (memory); (3) spinal cord disorders such as spinal cord injury, spinal cord space-occupying lesions, spinal cord atrophy, or paraplegia; (4) peripheral neuropathy & other Peripheral nervous system disorders; (5) cranial nerve disorder such as Trigeminal neuralgia; (6) autonomic nervous system disorders such as dysautonomia, multiple system atrophy; (7) seizure disorders such as epilepsy; (8) movement disorders of the central and peripheral nervous system such as Parkinson's disease, amyo
  • MS multiple sclerosis
  • prion diseases a type of infectious agent
  • CRPS complex regional pain syndrome
  • degenerative disorders such as vertebrae degeneration or spinal cord atrophy
  • sequela such as myelitis sequelae and brain trauma sequelae
  • motor neuron disease such as myelitis sequelae and brain trauma sequelae
  • hereditary ataxia or any known disorders or diseases in the art. Subjects with any particular neural disorders may be selected or excluded for the therapeutic uses and methods used herein.
  • spinal cord disorders in particular spinal cord injury and spinal cord space-occupying lesions
  • sequelae in particular myelitis sequelae and particular brain trauma sequelae
  • stroke also known as cerebral vascular accident (CVA), or cerebrovascular attack
  • motor neuron disease cerebral palsy and hereditary ataxia
  • UCBMSCs UCBMSCs transplantation at least three times.
  • At least one of the three UCBMSCs transplantations is via IV infusion plus intrathecal injection.
  • at least two of the three UCBMSCs transplantations are via IV infusion plus intrathecal injection.
  • spinal cord injury is most preferred.
  • spinal cord disorders may be treated, such as spinal cord injury or spinal cord space-occupying lesions.
  • spinal cord dystrophy or vertebrae degeneration may be treated in different or same subjects.
  • sequelae may be treated, particularly myelitis sequelae and brain trauma sequelae.
  • stroke may be treated.
  • motor neuron disease may be treated.
  • cerebral palsy may be treated.
  • hereditary ataxia may be treated.
  • SCI Spinal cord injury
  • Spinal cord injury refers to any injury to the spinal cord that is caused by trauma instead of disease (Taber et al. (2009), Taber's cyclopedic medical dictionary. F.A. Davis, pp. 2173-4). Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence (Lin et al. (2002). Spinal Cord Medicine: Principles and Practice. Demos Medical Publishing and Kirshblum et al. (2001 ), Spinal Cord Medicinem, Lippincott Williams & Wilkins). Spinal cord injuries are described at various levels of "incomplete”, which can vary from having no effect on the patient to a "complete” injury which means a total loss of function. Spinal cord injuries have many causes, but are typically associated with major trauma from motor vehicle accidents, falls, sports injuries, and violence.
  • SCIs are neurologically classified according to an international standard published by the American Spinal Injury Association (ASIA) (see Kirshblum et al. (2011), J Spinal Cord Med, 34(6): 535-546). According to this standard the location of the spinal cord injury is classified as follows:
  • T11 - Midclavicular line and the eleventh IS (midway between T10 and TI2)
  • S4-5 - Perianal area less than one cm, lateral to the mucocutaneous junction (taken as one level) Spinal cord injury at any one of these locations may be treated in accordance with the therapeutic use and method in certain aspects of the present invention.
  • This standard - being classified via the cord segments affected by the SCI - is also referred to in the examples herein below.
  • spinal cord space-occupying lesions refers to any injury of the spinal cord that is caused by disease instead of trauma. Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence. Spinal cord injuries are described at various levels of "incomplete”, which can vary from having no effect on the patient to a “complete” injury which means a total loss of function.
  • Current treatment of spinal cord space-occupying lesions starts with restraining the spine and controlling inflammation to prevent further damage and possible treatment to remove the original lesions such as tumor and inflammation. The current treatment can vary widely depending on the location and extent of the injury.
  • Sequelae is a pathological condition resulting from a disease, injury, therapy, or other trauma.
  • a sequelae is a chronic condition that begins during an acute condition.
  • Myelitis sequelae is an infection of the central nervous system caused by a virus, germ or parasite.
  • Patients with have sequelae of encephalitis because of the damage/ degeneration of the nervous system.
  • the main symptoms include motor disturbance, dysphasia, seizure and intelligence deficit.
  • Brain trauma sequelae is also known as traumatic brain injury (TBI), or intracranial injury in the art. TBI occurs when an external force traumatically injures the brain.
  • TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area).
  • TBI is a major cause of death and disability worldwide, especially in children and young adults. Causes include falls, vehicle accidents, and violence.
  • Brain trauma can be caused by a direct impact or by acceleration alone.
  • brain trauma causes secondary injury, a variety of events that take place in the minutes and days following the injury. These processes, which include alterations in cerebral blood flow and the pressure within the skull, contribute substantially to the damage from the initial injury.
  • TBI can cause a host of physical, cognitive, social, emotional, and behavioral effects, and outcome can range from complete recovery to permanent disability or death.
  • the 20 th century saw critical developments in diagnosis and treatment that decreased death rates and improved outcome.
  • Some of the current imaging techniques used for diagnosis and treatment include CT scans computed tomography and MRIs.
  • treatment required may be minimal or may include interventions such as medications, emergency surgery or surgery.
  • Physical therapy, speech therapy, recreation therapy, occupational therapy and vision therapy may be employed for rehabilitation.
  • a stroke, or cerebrovascular accident (CVA) is the rapid loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a haemorrhage. As a result, the affected area of the brain cannot function, which might result in an inability to move one or more limbs on one side of the body, inability to understandor formulate speech, or an inability to see one side of the visual field.
  • a stroke is a medical emergency and can cause permanent neurological damage and death. Risk factors for stroke include old age, high blood pressure, previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, tobacco smoking and atrial fibrillation.
  • TIA transient ischemic attack
  • High blood pressure is the most important modifiable risk factor of stroke.
  • An ischemic stroke is currently occasionally treated in a hospital with thrombolysis, and some haemorrhagic strokes benefit from neurosurgery.
  • Treatment to recover any lost function is termed stroke rehabilitation, ideally in a stroke unit and involving health professions such as speech and language therapy, physical therapy and occupational therapy.
  • Prevention of recurrence may involve the administration of antiplatelet drugs such as aspirin and dipyridamole, control and reduction of high blood pressure, and the use of statins.
  • Motor neuron diseases (also called sometimes amyotrophic lateral sclerosis (ALS) in the art) are a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscle activity including speaking, walking, swallowing, even breathing and general movement of the body. They are generally progressive in nature, and cause increasingly debilitating disability and, eventually, death. In around 95% of cases - there is no known cause for MND.
  • Riluzole (Rilutek) is the only treatment that has been found to improve survival but only to a modest extent. It also extends the time before a person needs ventilation support. Riluzole does not reverse the damage already done to motor neurons.
  • Other treatments for MND are designed to relieve symptoms and improve the quality of life for patients.
  • Cerebral palsy is an umbrella term denoting a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement. Scientific consensus still holds that CP is neither genetic nor a 'condition', and it is also understood that the vast majority of cases are congenital, coming at or about the time of birth, and/or are diagnosed at a very young age rather than during adolescence or adulthood. Cerebral refers to the cerebrum, which is the affected area of the brain. The disorder may often involve connections between the cortex and other parts of the brain such as the cerebellum.
  • palsy in the meaning of cerebral palsy refers to disorder of movement.
  • spasy in the term cerebral palsy makes it important to note that paralytic disorders are in fact not cerebral palsy. This means that the condition of quadriplegia, which comes from spinal cord injury or traumatic brain injury, should not be confused with spastic quadriplegia. Likewise, tardive dyskinesia should not be confused with dyskinetic cerebral palsy, or the condition of (paralytic) "diplegia” with spastic diplegia. Cerebral palsy's nature as a broad category means it is defined mostly via several different subtypes, especially the type featuring spasticity, and also mixtures of those subtypes.
  • Cerebral palsy is caused by damage to the motor control centers of the developing brain and can occur during pregnancy, during childbirth or after birth up to about age three. Resulting limits in movement and posture cause activity limitation and are often accompanied by disturbances of sensation, depth perception, and other sight-based perceptual problems, communication ability; impairments can also be found in cognition, and epilepsy is found in about one-third of cases. CP is often accompanied by secondary musculoskeletal problems that arise as a result of the underlying disorder. Ataxia is a neurological symptom comprising of a lack of voluntary coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum.
  • Ataxia may depend on hereditary disorders consisting of degeneration of the cerebellum and/or of the spine; most cases feature both to some extent, and therefore present with overlapping cerebellar and sensory ataxia, even though one is often more evident than the other.
  • Hereditary disorders causing ataxia include autosomal dominant ones such as spinocerebellar ataxia, episodic ataxia, and Dentatorubral-pallidoluysian atrophy (DRPLA), as well as autosomal recessive disorders such as Friedreich's ataxia (sensory and cerebellar, with the former predominating) and Niemann Pick disease, ataxia-telangiectasia (sensory and cerebellar, with the latter predominating), and abetalipoproteinaemia.
  • An example of X-linked ataxic condition is the rare fragile X-associated tremor/ataxia syndrome.
  • subject or “patient” is meant any single subject for which therapy is desired, including humans, primates, mice, rats, cattle, dogs, guinea pigs, rabbits, chickens, and so on. Also intended to be included as a subject are any subjects involved in clinical research trials not showing any clinical sign of disease, or subjects involved in epidemiological studies, or subjects used as controls.
  • the class "mammals” is divided into two subclasses based on reproductive techniques: egg- laying mammals (monotremes) and mammals which give live birth (therians).
  • the latter subclass is divided into two infraclasses: pouched mammals (marsupials) and placental mammals (eutherians).
  • Placental mammals which are used in some aspects of the invention all bear live young, which are nourished before birth in the mother's uterus through a specialized embryonic organ attached to the uterus wall, the placenta.
  • the placenta connects to the fetus by an umbilical cord.
  • the umbilical cord inserts into the chorionic plate (has an eccentric attachment).
  • the umbilical cord blood MSCs used in certain aspects of the invention are obtained from the umbilical cord.
  • the umbilical cord also called the birth cord or funiculus umbilicalis
  • the umbilical cord is a conduit between the developing embryo or fetus and the placenta.
  • the umbilical cord is physiologically and genetically part of the fetus and (in humans) normally contains two arteries (the umbilical arteries) and one vein (the umbilical vein), buried within Wharton's jelly.
  • the umbilical vein supplies the fetus with oxygenated, nutrient-rich blood from the placenta.
  • the fetal heart pumps deoxygenated, nutrient-depleted blood through the umbilical arteries back to the placenta.
  • the Wharton's jelly is a gelatinous substance made largely from mucopolysaccharides. It contains (in humans) one vein, which carries oxygenated, nutrient-rich blood to the fetus, and two arteries that carry deoxygenated, nutrient-depleted blood away.
  • the UCBMSCs are obtained from an umbilical cord after birth and from an umbilical cord which is physiologically occluded (either naturally or via clamp) from the fetus, for example cut off the fetus.
  • the umbilical cord blood MSCs used in the therapeutic use or method in certain aspects of the invention are obtained from the blood of the umbilical cord.
  • the blood is obtained from the umbilical cord and then the UCBMSCs are obtained from the umbilical cord blood.
  • Umbilical cord blood is a sample of blood taken from a newborn baby's umbilical cord. It is a rich source of stem cells, which to date have been used in the treatment of over 75 diseases, including leukemia, lymphoma and anemia.
  • Cord blood is obtained by syringing out the placenta through the umbilical cord at the time of childbirth, in general after the cord has been detached from the newborn.
  • Cord blood is collected because it contains stem cells, including hematopoietic cells and mensenchymal stem cells, which can be used to treat hematopoietic and genetic disorders.
  • One unit of cord blood generally usually provides stem cells in a quantity sufficient to treat an adult patient.
  • cord blood is a rich source of mesenchymal stem cells (MSC).
  • MSC mesenchymal stem cells
  • ISCT International Society of Cellular Therapy
  • MSC must be plastic-adherent when maintained in standard culture conditions.
  • MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11 b, CD79alpha or CD19 and HLA-DR surface molecules.
  • MSC must differentiate into osteoblasts, adipocytes and chondroblasts in vitro. These criteria may require modification as new knowledge unfolds. It is, though, currently believed that this minimal set of standard criteria fosters a more uniform characterization of MSC.
  • Harvesting the tissue of the umbilical cord can yield between 21 and 500 million MSC (Schugar et al (2009), J Biomed Biotechnol, 2009:789526, doi: 10.1 55/2009/7895269).
  • Umbilical cord blood (UCB)-derived mesenchymal stem cells are self-renewing multipotent progenitors with the potential to differentiate into multiple lineages of mesoderm, in addition to generating ectodermal and endodermal lineages by crossing the germline barrier.
  • UCBMSCs are capable to expand and differentiate into neurons (Divya et al (2012), Stem Cell Research & Therapy, 3:57).
  • the collection of mesenchymal stem cells (MSCs) from UCB is a well-established, easy, non-expensive and non-invasive method to collect MSCs (Chang et al. (2006), Cell Biol Int, 30:495-499).
  • Treatment and “treating” refer to administration or application of a therapeutic agent such as cells to a subject or performance of a procedure or modality on a subject for the purpose of obtaining a therapeutic benefit of a disease or health-related condition.
  • a treatment may include administration of an effective amount of cells that reduces the symptoms of a neural disorder.
  • the cells may be comprised in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference).
  • preservatives e.g., antibacterial agents, antifungal agents
  • isotonic agents e.g., absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like
  • solutions may be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.
  • the composition suitable for administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent.
  • a pharmaceutically acceptable carrier with or without an inert diluent.
  • examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof.
  • the composition may be combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
  • a composition in certain aspects of the invention may include a substantially pure population of MSCs or the progeny thereof.
  • the composition may also include or exclude cell culture components, e.g., culture media including one or more of amino acids, metals and coenzyme factors.
  • the composition may include small populations of other stromal cells.
  • the composition may also include or exclude other non-cellular components which may support the growth and survival of the MSCs under particular circumstances, e.g. implantation, growth in continuous culture, or use as a biomaterial or composition.
  • the composition may comprise a population of cells in which at least or at most about 25%, at least or at most about 30%, at least or at most about 35%, at least or at most about 40%, at least or at most about 45%, at least or at most about 50%, at least or at most about 55%, at least or at most about 60%, at least or at most about 65%, at least or at most about 70%, at least or at most about 75%, at least or at most about 80%, at least or at most about 85%, at least or at most about 90%, at least or at most about 95%, at least or at most about 96%, at least or at most about 97%, at least or at most about 98%, or at least or at most about 99%, of the cells are MSCs or any range or value derivable therein, either calculated by number, or by weight or by volume of the composition.
  • At least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, of the cells in the composition are MSCs or any range or value derivable therein, either calculated by number, or by weight or by volume of the composition.
  • the cell for administration may be in the range of 1x10e5 cells/mL to 1x10e6 cells/mL, 1x10e7 cells/mL to 1x10e8 cells/mL, 1x10e8 cells/mL to 1x10e9 cells/mL, 1x10e9 cells/mL to 1x10e10 cells/mL, 1x10e10 cells/mL to 1x10e11 cells/mL, or 1x10e11 cells/mL to 1x10e12 cells/mL or any range or value derivable therein.
  • the cells to be administered may include at least, about, or at most 1x10e5, 1x10e6, 1x10e7 cells/mL, 1x10e8, 1x10e9, 1x10e10 cells/mL, 1x10e11 , 1x10e12 cells or particularly MSCs.
  • the actual dosage amount of a composition or cells administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • At least, about or at most 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, or 168 hours, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 1000 ml (or any value or range derivable therein) of cells or composition may administered in total for the same subject, at each administration, at each injection, or at each infusion.
  • the MSCs may express one or more (e.g. two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) of the markers CD9, CD10, CD13, CD29, CD44, CD49A, CD51 , CD54, CD55, CD58, CD59, CD90 and CD105 at a significant level.
  • the MSCs may express one or more (e.g. two or more, three or more or four or more) of the markers CD9, CD44, CD54, CD90 and CD105,
  • the term “expressed” is used to describe the presence of a marker within a cell. In order to be considered as being expressed, a marker must be present at a detectable level. By “detectable level” is meant that the marker can be detected using one of the standard laboratory methodologies such as PCR, blotting or FACS analysis.
  • the phenotypic surface marker characterization of a population of MSCs may be performed by any method known in the art. By way of example, but not limitation, this phenotypic characterization may be performed by individual cell staining. Such staining may be achieved through the use of antibodies.
  • Antibody binding may be detected by any method known in the art. Antibody binding may also be detected by flow cytometry, immunofluorescence microscopy or radiography.
  • Cells or compositions may be administered to the same subject at least, about or at most 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 100 times or any range or value derivable therein.
  • the interval may be at least, about or at most 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, or 168 hours, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, or 60 days, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24,
  • the time between obtaining of isolated cells and administration may be at least, about, or at most 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, or 168 minutes or hours or any range derivable therein.
  • cells or compositions can be administered via targeted delivery, intravenously, intradermally, transdermal ⁇ , intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, mucosally, orally, topically, locally, inhalation (e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • targeted delivery like imaging-guided techniques such as with fluoroscopy or computed tomography (CT) may be used to increase the precision of these procedures and help confirm needle placement. Because imaging-guided techniques may lead to better results and reduced complication rates, they may be used for targeted delivery of cells into the injury site.
  • the target delivery method may be combined with one or more other administrations for the treatment of a neural disorder, such as intravenous or intrathecal procedures.
  • the claimed therapeutic uses and methods for treating a subject can be used in combination with another administration route, therapeutic agent or therapy method.
  • the subject has one or more neural disorders
  • the other agent or therapy is another agent or therapy for treating the neural disorder.
  • Treatment with the claimed dual or multiple administrations of cells may precede or follow the other therapeutic uses or therapy method by intervals ranging from minutes to weeks or any value or range derivable therefrom.
  • a therapeutic agent or method may be administered within about 1 minute to about 48 hours or more prior to and/or after administering the claimed dual or multiple administrations of cells, or prior to and/or after any amount of time not set forth herein.
  • the claimed dual or multiple administrations of cells may be administered within or from about 1 day to about 21 days prior to and/or after administering another therapeutic modality, such as another spinal cord injury therapy or any neural treatment. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several weeks ⁇ e.g., about 1 to 8 weeks or more) lapse between the respective administrations.
  • the claimed agent for dual chemotherapy and radiation therapy is derivative is "A” and the secondary agent, which can be any other therapeutic agent or method, is "B":
  • IV infusion also called phleboclysis, venoclysis and intravenous feeding in the art
  • IV infusion means that a solution is administered into a vein of a placental through an infusion set that includes, for example, a plastic or glass vacuum bottle or bag containing the solution and tubing connecting the bottle to a catheter or a needle in the patient's vein.
  • Intravenous infusion administration of fluids into a vein may be by means of a steel needle or plastic catheter.
  • a standard IV infusion set consists of a pre-filled, sterile container (glass bottle, plastic bottle or plastic bag) of fluids with an attachment that allows the fluid to flow one drop at a time, making it easy to see the flow rate (and also reducing air bubbles); a long sterile tube with a clamp to regulate or stop the flow; a connector to attach to the access device; and Y-sets to allow "piggybacking" of another infusion set onto the same line.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition can also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection.
  • the administration of stem cells via IV infusion is described, for example, in Min et al. (2006), J Thorac Cardiovasc Sur., (4):889-97.
  • lumbar puncture e.g., a needle is inserted between two lumbar bones (vertebrae)
  • intraventricular route e.g., a needle is inserted between two lumbar bones (vertebrae)
  • Intrathecal injection as used herein is an injection of the cells through the theca of the spinal cord into the subarachnoid space.
  • the subepidural space is the area which surrounds the spinal cord and the nerves coming out of it.
  • Means and compositions for intrathecal injection are known in the art, for example, from Qweider et al. (2007), Spine 6 (3): 280-3 or "Route of Administration", Data Standards Manual, Food and Drug Administration). For example, these injections have been used for treating people with low back ailments since 1952.
  • the administration of mesenchymal stem cells via intrathecal injection is described, for example, in Kim et al. (2010), Neurosci Lett, 468:190-4. The injection is usually done under local anesthesia.
  • the therapeutic use or method for treating spinal cord injury in accordance with certain aspects of the present invention has several advantages which may be summarized as follows: (i) No HLA matched umbilical cord blood stem cells may need to be transplanted to the patient suffering from spinal cord injury, (ii) The cord blood stem cells may need not be cultured and expanded in vitro, (iii) The treatment of spinal cord injury may be divided into complete spinal cord injury and incomplete spinal cord injury.
  • IV infusion plus intrathecal injections are in accordance with certain aspects of the present invention used to transplant stem cells to the patients.
  • the patients with spinal cord injury may receive said cell transplantation (IV infusion plus intrathecal injections) three times.
  • the first and third cell transplantation is the same for patients having a complete or incomplete spinal cord injury, namely IV infusion plus intrathecal injections.
  • IV infusion, intrathecal injection and in addition CT-guided injection that directly inject the stem cells to the injured spinal cord sites may be used if the patient has a complete spinal cord injury.
  • UCB human leukocyte antigen type
  • HLA human leukocyte antigen type
  • UCB contains enough stem cells and need not be expanded in vitro, which spares time and avoids the increased risk of contamination with any culture manipulation.
  • the stem cells can be isolated from UCB without culturing and directly transplanted to the patients.
  • UCBMSCs can be expanded in vitro. If the cells are expanded in vitro they retain the low immunogenicity and an immunomodulatory effect.
  • cells derived from the UCB elicit a lower incidence of graft rejection and post- transplant infections compared with other sources (Knutsen et al. (1999), J Allergy Clin Immunol 1999, 103:823-832).
  • the SCI treatment in certain aspects of the invention involves administration of UCBMSCs by IV infusion and intrathecal injection. Since intrathecal injection delivers the UCBMSCs directly to the spinal cord and consequently close to the side of the SCI, there was no motivation in the art to administer the UCBMSCs in addition by IV infusion, let alone in the expectation of any improvement.
  • the blood-brain-barrier segregates the blood and brain/spinal cord (Gabathuler (2010), Neurobiology of Disease 37 (2010) 48-57).
  • intravenously administered UCBMSCs have to get to and pass the BBB in order to reach the spinal cord injury sites while intrathecal injected UCBMSCs are directly injected into the spinal cord and thus close to the spinal cord injury sites.
  • intravenously administered MSCs get to and accumulate in lesions within the brain parenchyma and then transmigrate across the BBB (Matsushita et al. (2011 ), Neuroscience Letters, 502(1)41-45).
  • the cells are concomitantly or subsequently administered by intravenous administration such as infusion and intrathecal administration such as injection.
  • Concomitant administration means administration at the same time. Since intrathecal injection takes only a few minutes while IV infusion may take considerably longer, it has to be understood that intrathecal injection may be effected at any time during IV infusion. In this embodiment, the timing of intravenous infusion and intrathecal injection may also overlap. Since intrathecal injection takes only a few minutes the overlap in time is with increasing preference less than 5 min, less than 3min, and less than 1 min or any value or range derivable therein. Subsequently administration means that intravenous infusion is done after intrathecal injection or intrathecal injection is effected after intravenous infusion. Accordingly, there is no overlap in time when the IV infusion on the one hand and the intrathecal injection on the other hand are carried out.
  • the intermediate time may be in the range of seconds, minutes, hours of even days.
  • the intermediate time is with increasing preference less than 3 days, less than 2 days, less than 1 day, less than 12h, less than 6h, less than 4h, less than 3h, less than 2h, less than 1h, less than 30min, less than 15min, less than 10min and less than 5min, or any value or range derivable therein.
  • the umbilical cord blood derived mesenchymal stem cells are of the same species as the placental mammal in need of treatment.
  • a species is one of the basic units of biological classification and a taxonomic rank.
  • a species is in accordance with the invention defined as a group of organisms capable of interbreeding and producing fertile offspring. This embodiment can be cominbed with all embodments of the invention described herein further down.
  • the subject or placental mammal is human.
  • the placental mammal is particularly a human in accordance with certain embodiments of the invention.
  • this embodiment can be combined with all the remainder embodiments of the invention.
  • UCBMSCs mammalian umbilical cord blood derived mesenchymal stem cells
  • SCI spinal cord injury
  • the cells are to be administered by (i) intravenous infusion, and (ii) intrathecal injection, wherein the cells are concomitantly or subsequently administered by intravenous infusion and intrathecal injection.
  • a method for treating spinal cord injury (SCI) in a human in need of treatment comprising administering to the mammal umbilical cord blood derived mesenchymal stem cells (UCBMSCs), wherein said cells are administered by (i) intravenous infusion, and (ii) intrathecal injection, wherein the cells are concomitantly or subsequently administered by intravenous infusion and intrathecal injection.
  • UCBMSCs mammal umbilical cord blood derived mesenchymal stem cells
  • SCI spinal cord injury
  • UCBMSCs mammal umbilical cord blood derived mesenchymal stem cells
  • a therapeutic use and method for treating spinal cord injury (SCI) in a human in need of treatment comprising administering to the mammal umbilical cord blood derived mesenchymal stem cells (UCBMSCs), wherein the cells are allogeneic cells and said allogeneic cells and the placental mammal in need of treatment are not HLA-matched prior to the treatment.
  • SCI spinal cord injury
  • UCBMSCs mammal umbilical cord blood derived mesenchymal stem cells
  • the spinal cord injury is incomplete spinal cord injury.
  • An incomplete SCI is an SCI where there is preservation of any sensory and/or motor function below the neurological level that includes the lowest sacral segments S4-S5 (i.e. presence of "sacral sparing" (see Kirshblum et al. (2011 ), J Spinal Cord Med, 34(6): 535-546).
  • Sensory sacral sparing includes sensation preservation (intact or impaired) at the anal mucocutaneous junction (S4-5 dermatome) on one or both sides for light touch or pin prick, or deep anal pressure (DAP).
  • Motor sacral sparing includes the presence of voluntary contraction of the external anal sphincter upon digital rectal examination.
  • the cells are administered each three times by intravenous infusion and intrathecal injection.
  • the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion and intrathecal injection.
  • the three times are each separated by one week intervals.
  • the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion and intrathecal injection.
  • each at the first, second and third time about 3x 10 8 cells are suspended in 5 ml saline solution, whereof 3 ml solution are intrathecal ⁇ injected and 2 ml are further suspended in 100 ml saline solution and subsequently intravenously infused.
  • 3 * 10 8 UCBMSCs are suspended in the 5 mL saline.
  • the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion and intrathecal injection.
  • This dosage regimen for the administration of UCBMSCs was used for the treatment of patients having an incomplete SCI in Example 1 herein below.
  • the spinal cord injury is complete spinal cord injury and the cells are furthermore directly injected into the injured spinal cord sites.
  • a complete SCI is an SCI where there is an absence of sensory and motor function in the lowest sacral segments (S4-S5) (i.e. no sacral sparing) (see Kirshblum et al. (2011 ), J Spinal Cord Med, 34(6): 535-546).
  • the direct injection of UCBMSCs into the injured spinal cord sites was done in accordance with example 1 herein below if the patient to be treated has a complete SCI.
  • Direct injection of UCBMSCs into the injured spinal cord sites may use a computed tomography (CT) guided injection. It has been surprisingly found in the context of the present invention (see the Examples herein below) that administering UCBMSCs by IV infusion, intrathecal injection and in addition directly into the sites of the SCI further significantly improves the treating outcome of SCI patients, in particular SCI patients having a complete SCI.
  • CT computed tomography
  • the cells are administered each three times by intravenous infusion and intrathecal injection and at the second time the cells are furthermore directly injected into the injured spinal cord sites. It has to be understood that also in connection with this particular embodiment the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion, intrathecal injection and direct injected into the injured spinal cord sites.
  • the treatment may comprise three regimens, namely intravenous infusion, intrathecal injection and direct injected into the injured spinal cord sites. In further embodiments, two or all three regimens may be carried out concomitantly as defined herein above. Also in certain embodiments of the invention where the treatment comprises three regimens, namely intravenous infusion, intrathecal injection and direct injected into the injured spinal cord sites, two or all three regimens may be carried out subsequently as defined herein above.
  • the respective two regimens may be each independently IV infusion and intrathecal injection; IV infusion and direct injected into the injured spinal cord sites; or intrathecal injection and direct injected into the injured spinal cord sites.
  • the three times are each separated by one week intervals.
  • the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion, intrathecal injection, and direct injected into the injured spinal cord site.
  • the cells are suspended in 5 ml saline solution, whereof 3 ml solution are intrathecally injected and 2 ml are further suspended in 100 ml saline solution and subsequently intravenously infused
  • the cells are suspended in 5 ml saline solution, whereof 2 ml solution are intrathecal ⁇ injected, 2 ml are further suspended in 100 ml saline solution and subsequently intravenously infused and 1ml saline solution is directly injected into the injured spinal cord sites
  • the cells are suspended in 5 ml saline solution, whereof 3 ml solution are intrathecal ⁇ injected and 2 ml are further suspended in 100 ml saline solution and subsequently intravenously infused.
  • 3*10 8 UCBMSCs are suspended in the 5mL saline.
  • the cells can be concomitantly or subsequently administered as defined herein above by intravenous infusion, intrathecal injection, and direct injected into the injured spinal cord site.
  • This dosage regimen for the administration of UCBMSCs was used for the treatment of patients having a complete SCI in Example 1 herein below.
  • the cells are used directly after isolation without expansion for the treatment.
  • UCB contains enough stem cells and need not be expanded in vitro, which spares time and avoids the increased risk of contamination with any culture manipulation.
  • the cells are allogeneic cells and said allogeneic cells and the placental mammal in need of treatment are not HLA-matched prior to the treatment.
  • UCB cells in general do not induce (an adverse) immunological response in a subject although HLA type has not been matched.
  • the therapeutic use and method is combined with a further therapeutic use and method of treatment, such as a laminectomy.
  • Laminectomy is a surgical procedure to remove a portion of the vertebral bone called the lamina.
  • the minimal form of the procedure requires only small skin incisions, the back muscles are pushed aside rather than cut, and the parts of the vertebra adjacent to the lamina are left intact. Recovery from the minimal procedure can occur within a few days.
  • laminectomy is effected prior to the IV infusion, intrathecal injection, and/or if carried out direct injection into the SCI sites.
  • laminectomy is effected after or inbetween the IV infusion, intrathecal injection, and/or if carried out direct injection into the SCI sites
  • the further therapeutic use or method of treatment may be any additional therapeutic use or method of treatment, respectively, the placental mammal is in need of.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • the phrase “consisting of” excludes any element, step, or ingredient not specified in the claim except for, e.g., impurities ordinarily associated with the element or limitation.
  • the term “or combinations thereof as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.
  • words of approximation such as, without limitation, "about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as "about” may vary from the stated value by at least +1 , 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • each embodiment mentioned in a dependent claim/item is combined with each embodiment of each claim/item (independent or dependent) said dependent claim depends from.
  • a dependent claim 2 reciting 3 alternatives D, E and F and a claim 3 depending from claims 1 and 2 and reciting 3 alternatives G, H and I
  • the specification unambiguously discloses embodiments corresponding to combinations A, D, G; A, D, H; A, D, I; A, E, G; A, E, H; A, E, I; A, F, G; A, F, H; A, F, I; B, D, G; B, D, H; B, D, I; B, E, G; B, E, H; B, E, I; B, F, G; B, F, H; B, F, I; C, D, G; C, D, H;
  • Figure 1 Shows the percentage of patients with a spinal cord injury, spinal cord space- occupying lesions, brain trauma sequelae, stroke (CVA), motor neuron disease, cerebral palsy, and hereditary ataxia, respectively, which showed improvement when treated under the administration protocols according to Examples 1 and 1 1 to 16, respectively. Depending on the particular disease to be treated between 90 and 100% of patients showed an improvement.
  • cells isolated from UCBMSCs are transplanted to treat complete SCI (no any motor or sensory function) and incomplete SCI (incomplete motor or sensory function).
  • cells are collected from UCB by density gradient centrifugation and suspended in saline.
  • cells are transplanted to the patients through three ways: intravenous infusion, intrathecal injection and - in case of complete SCI - CT-guided injection that directly targeted the lesion sites.
  • the situations of the patients are evaluated from the following aspects: muscle power, muscle tone, sensory function, urinary and bowel function, function and erectile dysfunction.
  • Examples 11 to 16 describe administration protocols for spinal cord space-occupying lesions, brain trauma sequelae, stroke (CVA), motor neuron disease, cerebral palsy, and hereditary ataxia, respectively.
  • Umbilical Cord Blood (100-150 ml_) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procurement guidelines for cord blood in each hospital. Blood samples are processed within 4 hours.
  • Step (h) Discard the supernate, resuspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • IV infusion plus intrathecal injections was used to transplant stem cells to the patients with incomplete spinal cord injury.
  • the stem cells were suspended in
  • the patients with complete spinal cord injury receive cell transplantation three times, too.
  • the first and third cell transplantation are as well as those in incomplete spinal cord injury.
  • cord blood stem cells were not cultured and expanded in vitro.
  • the spinal cord injury has been divided to complete and incomplete spinal cord injury.
  • IV infusion plus intrathecal injections was usually used to transplant stem cells to the patients with incomplete spinal cord injury.
  • the patients with complete spinal cord injury receive cell transplantation three times, too.
  • the first and third cell transplantation are as well as those in incomplete spinal cord injury.
  • IV infusion, intrathecal injection and CT-guided injection that directly inject the stem cells to the injured spinal cord sites were used.
  • Example 2 Treatment of spinal cord atrophy and thoracic vertebrae degeneration in T11-12
  • his motor power of lower limps was 0; his pain below bilateral T11 and his tactile below bilateral T12 disappeared; and he had urinary and bowel dysfunction.
  • his motor power of lower limps was 2; his gluteus maximums could contract after his left anus was stimulated; he could discharge urine and stool under the pressure of abdominal; his sexual function restored partly.
  • Example 4 Treatment of high paraplegia
  • a 31 year old Asian male patient diagnosed with high paraplegia had a C5, 6, 7 vertebral fractures caused by car accident, which resulted in limited upper extremity activities and independent lower extremity activities.
  • his motor power of proximal upper limbs is 5 and distal is 2; his motor power of lower limps was 0; his muscle tone increased; his stool was dry and his urine depended on urethral catheterization.
  • his motor power of proximal right lower limp was 4 and distal was 3; his motor power of proximal left lower limp was 3+ and distal was 2+; his left lower limp could lift by himself; and the pain of his lower limps relieved greatly.
  • Example 6 Treatment of complete spinal cord injury
  • her motor power of left lower limp was 4; her motor power of right lower limp was 3-; her muscle tone of lower limps increased and the right lower limp was more serious than the left; her tendon reflex of upper limps was active and lower limps was hyperactive; and the tendon reflex of her right side of body was more serious than her left.
  • her motor power of left lower limp was 4+ and right was 3+; her muscle tone of lower limps became normal; her stool became smooth and once a day regularly; her urine could be voided autonomously but not entirely; her sense of stool and urine became normal.
  • his motor power of lower limps was 0; his muscle tone decreased; his dual knee and ankle reflexes disappeared. His feeling between T11 and T12 decreased and below T12 disappeared; his stool was incontinent; and he needed intermittent catheterization.
  • Example 11 Administration protocol for for spinal cord space-occupying lesions
  • UCB (100 ⁇ 150 mL) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours.
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • the pregnant donor women undergo medical examinations before they donate UCB.
  • the donors are ensured healthy people without communicable diseases such as HBV, HCV, HIV and Syphilis.
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • Intravenous (IV) infusion plus intrathecal injections are used to transplant stem cells to the patients with incomplete spinal cord injury.
  • the mononuclear cells containing stem cells are suspended in 5 ml saline solution.
  • the 3 ml solution are injected into cerebrospinal fluid (CSF).
  • CSF cerebrospinal fluid
  • the remaining 2 ml solution are suspended in 100 ml saline solution for IV infusion.
  • the treatments are performed three times and separated by one week intervals.
  • the patients with complete spinal cord injury receive cell transplantation three times, too.
  • the first and third cell transplants are the same as those in incomplete spinal cord injury.
  • IV infusion, intrathecal injection and CT-guided injection that directly target the injured spinal cord site are employed.
  • the mononuclear cells containing stem cells are suspended in 5 ml saline solution, 2 ml solution for IV infusion, 2 ml for intrathecal injection and 1 ml for CT-guided injection that directly injected to the in juried site of spinal cord.
  • the UCB stem cells are not cultured and expanded in vitro.
  • Example 12 Administration protocol for for brain trauma sequelae (A) Isolation of mononuclear cells containing stem cells from UCB
  • UCB (100-150 mL) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours.
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • the pregnant donor women undergo medical examinations before they donate UCB.
  • the donors are ensured healthy people without communicable diseases such as HBV, HCV, HIV and Syphilis.
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • UCB (100-150 mL) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours.
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • the pregnant donor women undergo medical examinations before they donate UCB.
  • the donors are ensured healthy people without communicable diseases such as HBV, HCV, HIV and Syphilis.
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • CVA CVA
  • Stem cell transplantations ameliorate patients symptom's to a certain extent (see Figure 1 ). Some patients could be totally back to their normal lives.
  • Example 13 Administration protocol for motor neuron diseases (A) Isolation of mononuclear cells containing stem cells from UCB
  • UCB (100-150 ml_) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours.
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • Example 14 Administration protocol for cerebral palsy
  • UCB (100-150 mL) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours. 2. Isolation of mononuclear cells containing stem cells from UCB
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • the pregnant donor women undergo medical examinations before they donate UCB.
  • the donors are ensured healthy people without communicable diseases such as HBV, HCV, HIV and Syphilis.
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • Example 16 Administration protocol for hereditary ataxia (A) Isolation of mononuclear cells containing stem cells from UCB 1. Preparation of UCB
  • UCB (100-150 ml_) is collected from primiparous pregnant women receiving caesarean section in accordance with the sterile procedure guidelines in each hospital. UCB samples are processed within 4 hours.
  • Step (h) Discard the supernatant, re-suspend the cell pellet in PBS, and repeat the washing procedure, Step (g).
  • the pregnant donor women undergo medical examinations before they donate UCB.
  • the donors are ensured healthy people without communicable diseases such as HBV, HCV, HIV and Syphilis.
  • each blood sample is tested for communicable diseases such as HBV, HCV, HIV and Syphilis.
  • Hereditary Ataxia Due to the rapid progress of Hereditary Ataxia, it is recommended that the patients come back every year to get one more time stem cell transplant for reinforcement.
  • the protocol is improves the quality of life of patients and prolong the patient's life.
  • Hereditary Ataxia such as instability of gait, difficulty with eye movements, dysarthria, dysphagia, hypotonia, dyschronometria and dysdiadochokinesia are improved.
  • Stem cell transplantation is expected to ameliorate one's symptoms to a certain extent.
  • a method for treating spinal cord injury in a placental mammal in need of treatment comprising administering to the placental mammal umbilical cord blood derived mesenchymal stem cells, wherein said cells are administered by
  • a method for treating a neural disorder in a subject in need of treatment comprising administering to the subject a composition comprising an effective amount of umbilical cord blood derived mesenchymal stem cells, wherein said cells are administered by
  • a method for treating a neural disorder in a subject in need of treatment comprising administering to the subject a composition comprising an effective amount of umbilical cord blood derived mesenchymal stem cells, wherein said cells are administered by
  • composition comprises at most 10 7 , 10 8 , 10 9 , or 10 10 umbilical cord blood derived mesenchymal stem cells.
  • composition comprising a cell population comprises at least 50, 60, 70, 90, or 95% mesenchymal stem cells.

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Abstract

La présente invention concerne des cellules souches mésenchymateuses dérivées de sang de cordon ombilical (UCBMSC) destinées à être utilisées pour traiter un trouble neuronal chez un sujet, tel qu'un mammifère placentaire, lesdites cellules étant conçues pour être administrées par (i) administration intraveineuse et (ii) administration intrathécale. La présente invention concerne également un procédé pour traiter une lésion de moelle épinière (SCI) chez un mammifère placentaire ayant besoin d'un traitement, comprenant l'administration au mammifère de cellules souches mésenchymateuses dérivées de sang de cordon ombilical (UCBMSC), lesdites cellules étant administrées par (i) perfusion intraveineuse et (ii) injection intrathécale.
PCT/IB2014/059900 2013-03-15 2014-03-17 Transplantation de cellules souches dérivées de sang de cordon ombilical pour le traitement d'un trouble neuronal WO2014141219A1 (fr)

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WO2022147575A1 (fr) * 2021-01-04 2022-07-07 University Of Florida Research Foundation, Incorporated Méthodes et compositions de traitement de l'ataxie de friedreich
EP4190337A4 (fr) * 2020-07-31 2024-09-04 Neurotech Medical Co Ltd Agent thérapeutique de neuropathie
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