Xenotech presentation May 1 2008

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How to use placental or UCB stem cells as drug discovery tools in neuro-toxicology and other applications

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  • chemical signals (polypeptide growth factors and cytokines) in the local tissue environment control growth and specialization of different cell types of the prostate, the liver, the vascular system and neural tissue. These signals determine the normal development and function of the tissues while aberrations result in tissue dysfunction and diseases, such as cancer, stroke, atherosclerosis, liver, and neural disease. These signaling systems which are comprised of a signal polypeptide from one cell type and a reception system on another are the basis for communication among cells in tissues, but also serve as sensors of signals like hormones and nutrients that come from outside the tissues. The cellular reception system for many signal polypeptides consists of a transmembrane protein whose external domain interacts with signal polypeptides and an intracellular domain which is a protein kinase enzyme which activates metabolic pathways that control cell growth, function, and gene expression.
  • NFT = neurofibrillary tangles
    trkA = tyrosine kinase

    Thus, the phenomenon of apoptosis, that is central to the Neurotrophic Factor Hypothesis, was first observed in the context of the discovery of NGF and its role on differentiation and survival of sympathetic and sensory neurons of the peripheral nervous system [70,71]. During development, neurotrophins regulate neuronal survival and differentiation, and determine the pattern of innervation and the expression of proteins that are crucial to a specific neuronal phenotype, like neurotransmitters and neuropeptides, neurotransmitter receptors and ion channels. According to the neurotrophic hypothesis, the correct pattern of innervation is dependent upon competition of developing neurons for a limited supply of growth factors secreted by target tissues, thus ensuring a balance between the number of neurons and the size of the innervated target

    excitotoxicity due to overactivation of glutamate receptors represents a final common pathway for both acute neurological disorders, such as stroke, trauma and epileptic seizures, and chronic neurodegenerations like AD
  • Xenotech presentation May 1 2008

    1. 1.  Wittenberg University (BA)  University of Rochester  BRL/Life Technologies, Inc.  BP Solar  In Vitro Technologies  Gahaga, APE-BridgePath Scientific @ FITCI
    2. 2. $- $1,000 $2,000 $3,000 $4,000 $5,000 $6,000 $7,000 $8,000 $9,000 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 1961: Canadians Jim Till & Ernest McCulloch prove the existence of stem cells (Nature 1963) 1978: Hematopoietic SC discovered in UCB 1981: mouse ES cells isolated 1988: HSC isolated from blood 1992: Adult neural SC discovered 1994: first Cancer SC discovered 1996: Dolly the Sheep 1998: first human ES line RegMed 2.0 USD (millions)
    3. 3.  ES cells: › pluripotent › Limited number of cells and strains available › Regulatory environment › Political/ethical issues  “Adult” SC: › lineage dependant › Not easy to isolate or proliferate in sufficient quantities › Most widely used/accepted in clinical applications
    4. 4.  IPS (induced Pluripotent SCs) › Latest thing › Still a lot of uncertainty  Perinatal tissue: UCB & Afterbirth › Ephemeral organ › Not really “adult” › Pluripotent (?) › Easy to obtain in large volume, various donor demographics
    5. 5.  As a replacement for Primary Cells › Hepatocytes › Renal cells › Circulatory › Cardiomyocytes › Neurons › Pulmonary cells › Bone, cartilage › Skin: Wound healing & absorption models  In vitro models for metabolic homeostasis & Organogenesis › Demonstrate a “stimulation” of injury & repair mechanisms › Inhibition of necrosis/apoptosis › Tissue specific developmental pathways › Cancer Stem Cells
    6. 6.  The path of least resistance  Neurodegenerative diseases › Alzheimer's › Parkinson's › MS › ALS/Lou Gehrig's disease  Acute Injuries › Spinal cord injury › Stroke › Head injury › Cerebral Palsy  Abnormal Neural function › Depression › Epilepsy › Autism  HIV
    7. 7. The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration, BMC Neurosci. 2006; 7(Suppl 1): S2.
    8. 8.  From term amniotic membrane tissue  Primary, adherent cultures & cryopreserved  Mesenchymal morphology and Immunophenotype  Assessed differentiation side-by-side vs. Lonza bm-MSC  Assessed growth in proprietary GHG medium vs. Invitrogen MesenPRO® medium  Developed two-step differentiation protocol
    9. 9. GahagamediumInvitrogenMesenPRO©
    10. 10. GahagamediumInvitrogenMesenPRO©
    11. 11.  Grown to confluence in 96 well plates, with proprietary placental basement membrane extract  Differentiation for 4 days  7 days Neuronal maintenance in IVGN Neurobasal medium
    12. 12.  Establish clinical significance, IVIVC  Choosing the right target: pick one or two target assays most relevant in the field  Optimize isolation, differentiation protocols  Collaborate with one or more existing ADMET/DMPK companies  Always the issue of IP and litigation in this emerging field
    13. 13.  A readily obtainable & reproducible source of neuronal precursors and neurons for the study of neuronal function, dysfunction, and development  A culture system for neuronal differentiation  Potential for similar systems for other stromal cell types

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