Understanding brain diseases from stem cells to clinical trials
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1 Understanding brain diseases from stem cells to clinical trials Alan Mackay Sim Griffith Institute for Drug Discovery Griffith University Brisbane, QLD
2 Making ES cells Fertilise an egg Put in a dish Embryonic stem cell Get a blastocyst Put in a womb
3 Making ips cells from adult cells Induced pluripotent stem cell Wait Add factors Wait Put any cell in a dish
4 ES and ips cells are pluripotent ES and ips cells Put in a mouse or a dish Equals all the tissues in a person
5 ES and ips cells make eggs Hayashi et al (2011) Offspring from Oocytes Derived from in Vitro Primordial Germ Cell like Cells in Mice. Science, 338: Image from Cheloufi and Hocheldiniger, Nature, 2012, 491:535.
6 ES and ips cells make sperm Hayashi et al (2011) Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells. Cell, 146:
7 Grow an eye In a dish Eiraku et al, 2011, Nature Volkner and Karl, 2015, Stem Cell Reports
8 Lancaster et al, 2013, Nature Grow a brain
9 Grow a kidney In a dish Biology and drug discovery, not therapy Takatso et al, 2015, Nature
10 Patient derived ips cells (for regenerative medicine and drug discovery) Cell Transplantation transplantation Bellin et al (2012) ipscs: the new patient, Nature Rev Molecular Cell Biology 13:
11 Stem cell therapy: diabetes Beta cells are proving very hard to make from ES/iPS cells Transplanted cells cannot avoid the immune system NIH (2001) Stem Cells: Scientific Progress and Future Research Directions
12 Stem cell therapy: Parkinson s disease Foetal substantia nigra transplants were effective BUT Transplanted neurons get the disease pathology The disease is not cell autonomous The neurons are affected by their environment NIH (2001) Stem Cells: Scientific Progress and Future Research Directions
13 Cells in a bottle Fixing the injured spinal cord? Embryonic stem cells In a Phase I, safety trial but company (Geron) withdrew Oligodendrocyte precursors
14 Your own ( adult ) stem cells Haematopoietic stem cells Neural stem cells Mesenchymal stem cells Bone marrow stem cells Skin stem cells Gut stem cells
15 The boy in the bubble Curing genetic blood disorders Haematopoietic stem cells + genetic engineering Now being trialled for genetic metabolic diseases and autoimmune diseases
16 Stem cell therapy: autoimmune disease Haematopoietic stem cells are being trialled for autoimmune diseases Concept: Chemotherapy kills the HSCs Removes antibody making (B) cells Transplant healthy donor HSCs Risk: Death (Transplanted cells do not engraft) Benefit: Autoimmunity is eliminated Success: Multiple sclerosis NIH (2001) Stem Cells: Scientific Progress and Future Research Directions
17 Bioengineering Stem cells plus scaffolds Adult Stem Cell Breakthrough: First Tissue Engineered Trachea Successfully Transplanted Nov. 19, 2008 The first tissue engineered trachea (windpipe), utilising the patient's own stem cells, has been successfully transplanted into a young woman with a failing airway. The bioengineered trachea immediately provided the patient with a normally functioning airway, thereby saving her life. Not widely available! Scientist fired for ethical breaches
18 The oldest trick in the book 50 years of bone marrow transplants for blood diseases Haematopoietic stem cells Routine for many blood cancers
19 Doing what they do best Fixing bone and cartilage Bone marrow mesenchymal stem cells Still undergoing clinical trials to show proof of efficacy
20 More cells in a bottle Neural stem cells for the nervous system? Foetal brain Phase I trials for Spinal cord injury, macular degeneration, genetic brain diseases Neural stem cells
21 The commercial imperative Have liposuction, will travel Fat derived mesenchymal stem cells You can pay a lot for unproven treatments
22 Stem cells up the nose Accessible neural stem cells Spinal cord injury repair, cellular mechanisms of brain diseases, Stem cells for drug discovery
23 The olfactory apparatus Brain Olfactory bulb Olfactory mucosa
24 Neurogenesis Making new neurons in the olfactory epithelium Stem cells Olfactory ensheathing cells Mackay-Sim et al, 2013
25 Therapies up the nose Olfactory ensheathing cells Autologous (grow your own) to avoid the immune system
26 Spinal cord injury Phase I clinical trial in paraplegia Olfactory ensheathing cell transplantation is safe 1 year and 3 years later
27 Stem cells and brain diseases Brain diseases in a dish
28 Biology of Schizophrenia Hundreds of risk genes, many environmental risks Automated imaging Automated analysis over 24 hr Bernard Tee Yongjun Fan Cell functions controlling brain development are affected cell motility regulation is lost cell proliferation is faster gene expression is altered (1700 RNAs are affected) protein expression is altered (102 proteins are affected) protein synthesis rate is slowed Greger Abrahamsen
29 Drug discovery for Parkinson s disease Finding compounds that rescue patient cells from oxidative stress Cells + 96 well plates + Automated imaging and analysis + Automated chemical library Stephen Wood 350,000 pure compounds 200,000 natural products fractions George Mellick Tested ~ 40,000 compounds in 4224 fractions Pure compounds confirmed Before After Four new natural product compounds for drug development
30 Drug discovery for familial dysautonomia IKBAP gene mis spliced, IKBAP protein loss Patient derived IPSCs Patient derived neural crest cells 7000 compounds screened 8 hits All approved for other uses All increased IKBAP gene expression Lee et al, 2012, Nat Biotech
31 Drug discovery for Hereditary Spastic Paraplegia Control cell peroxisomes Patient cell peroxisomes Gautam Wali Yongjun Fan Gene mutation Slow peroxisomes Oxidative stress Neuron death Two drug candidates for clinical trials They speed up peroxisomes and prevent oxidative stress Both are approved for other uses Both are very safe at low doses required Carolyn Sue
32 Just past the beginning Routine clinical uses are still a long way away Safety and proof are required for every application
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