Understanding brain diseases from stem cells to clinical trials Alan Mackay Sim Griffith Institute for Drug Discovery Griffith University Brisbane, QLD
Making ES cells Fertilise an egg Put in a dish Embryonic stem cell Get a blastocyst Put in a womb
Making ips cells from adult cells Induced pluripotent stem cell Wait Add factors Wait Put any cell in a dish
ES and ips cells are pluripotent ES and ips cells Put in a mouse or a dish Equals all the tissues in a person
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: 971 975. Image from Cheloufi and Hocheldiniger, Nature, 2012, 491:535.
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, 146:519 532.
Grow an eye In a dish Eiraku et al, 2011, Nature Volkner and Karl, 2015, Stem Cell Reports
Lancaster et al, 2013, Nature Grow a brain
Grow a kidney In a dish Biology and drug discovery, not therapy Takatso et al, 2015, Nature
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 13:713 726.
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
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
Cells in a bottle Fixing the injured spinal cord? Embryonic stem cells In a Phase I, safety trial but company (Geron) withdrew Oligodendrocyte precursors
Your own ( adult ) stem cells Haematopoietic stem cells Neural stem cells Mesenchymal stem cells Bone marrow stem cells Skin stem cells Gut stem cells
The boy in the bubble Curing genetic blood disorders Haematopoietic stem cells + genetic engineering Now being trialled for genetic metabolic diseases and autoimmune diseases
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
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
The oldest trick in the book 50 years of bone marrow transplants for blood diseases Haematopoietic stem cells Routine for many blood cancers
Doing what they do best Fixing bone and cartilage Bone marrow mesenchymal stem cells Still undergoing clinical trials to show proof of efficacy
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
The commercial imperative Have liposuction, will travel Fat derived mesenchymal stem cells You can pay a lot for unproven treatments
Stem cells up the nose Accessible neural stem cells Spinal cord injury repair, cellular mechanisms of brain diseases, Stem cells for drug discovery
The olfactory apparatus Brain Olfactory bulb Olfactory mucosa
Neurogenesis Making new neurons in the olfactory epithelium Stem cells Olfactory ensheathing cells Mackay-Sim et al, 2013
Therapies up the nose Olfactory ensheathing cells Autologous (grow your own) to avoid the immune system
Spinal cord injury Phase I clinical trial in paraplegia Olfactory ensheathing cell transplantation is safe 1 year and 3 years later
Stem cells and brain diseases Brain diseases in a dish
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
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
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
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
Just past the beginning Routine clinical uses are still a long way away Safety and proof are required for every application