Stem cell therapies for brain disorders
Multiple Sclerosis, Alzheimer's, Stem cell therapies
Of the approximately 2.5 million patients diagnosed and living with multiple sclerosis (MS) globally, the impact of MS regarding quality of life (QOL) and global health burden increases significantly once patients convert from relapsing-remitting to Progressive MS and there exists a lack of tangible therapeutic options for the >50% of patients that progress even while on currently available FDA approved medications (15 available). Multiple sclerosis (MS) is commonly induced by the specific destruction of the protective sheath of nerve fibres, known as myelin, by immune cells, which mistakenly attack this structure. However, it has been shown that MS does not only consist of this disease pattern but is a multifactorial disease with continual destruction of the nerve fibres even without large numbers of immune cells invading the brain and the spinal cord. Importantly, the molecules which may contribute or initiate such damage in MS are becoming known and by targeting these molecules during MS it may be possible to limit the destruction which occurs to nerve fibres in the brain and spinal cord, promoting a better clinical outcome for individuals suffering with MS. We are investigating how damage occurs in nerve fibres with progressive clinical symptoms in the experimental animal model of MS and are targeting this mechanism to block the molecules that propagate the nerve fibre degeneration using novel stem cell-based strategies to deliver agents to the brain and spinal cord.
We have also initiated a drug development project for a repurposed drug with accelerated translation potential and path to market for Progressive Multiple Sclerosis, an unmet medical need. We are trialling a drug benchmarked against drugs of its class currently in clinical trials that may help promote the generation of new oligodendrocytes and myelin to promote neuroprotection and repair.
Alzheimer's disease (AD) is one of the most prevalent severe neurological disorders afflicting our aged population. Cognitive decline, a major symptom exhibited by AD patients, is associated with neuritic dystrophy, a degenerative growth state of neurites. The molecular mechanisms governing neuritic dystrophy remain unclear. Mounting evidence indicates that the AD-causative agent, β-amyloid protein (Aβ), induces neuritic dystrophy. Our group is investigating potential molecular pathways, which may be modulated subsequent to Aβ-dependent interactions with the neuronal membrane as a consequence of increasing amyloid burden in the brain.
Projects and Opportunities
Two (2) PhD positions are currently available (January 2020). Contact Steven Petratos, email@example.com
Project 1: For the first time, we will define a new role for a drug in enhancing brain repair during MS-like disease, used previously to treat people living with inherited neurological conditions. (i) We will identify how MS-like progressive symptoms can be limited by administering a drug that can reach the brain. We will specifically define the benefit this drug has in protecting cells from dying during MS-like disease. (ii) We will assess the feasibility of this drug that can readily enter the brain to exert repair by generating new cells and protecting nerve fibres. We will correlate this with clinically relevant parameters to assess the limitation of brain damage with the use of this drug. If this project is successful, and in particular, the drug is shown to be safe and efficacious in repairing the damaged brain, then the fact that it has already been tested in clinical phase trials means that a drug company can immediately trial the drug in MS patient groups that are not responding to other therapies. Therefore, this project will provide the proof-of-principle studies necessary for the drug to enter clinical phase trials in MS patients.
Project 2: This will be the first study to utilise and validate genetically modified haematopoietic stem cells as the therapeutic delivery system to minimise and reverse the impact of MS progression. The research strategy uses a novel means to deliver a biological reparative agent directly to neuroinflammatory lesions, where neurodegenerative disease can propagate. Given that clinical studies using autologous bone marrow or haematopoietic stem cells of individuals have demonstrated improvement in the outcomes of MS, our novel technological advance of using these cells to deliver treatments for nervous system repair are timely and innovative. Delivering biological agents directly to areas where the disease is active will be investigated in this project to specifically limit the damage that can cause disability. Moreover, future therapeutic development of this technology may benefit individuals living with progressive MS through attenuating the extracellular disease milieu to favour repair in the adult CNS.
See short list below or more publications at Dr Steven Petratos's profile
- Chiha W, Bartlett C, Petratos S, Fitzgerald M, Harvey AR (2020) Intravitreal application of AAV-BDNF or mutant AAV-CRMP2 protects retinal ganglion cells and stabilizes axons and myelin after partial optic nerve injury, Experimental Neurology (in press).
- Kim MJ and Petratos S. (2019) Oligodendroglial lineage cells in thyroid hormone-deprived conditions. Stem Cells International 2019:e5496891.
- Lee JY, Kim MJ, Thomas S, Oorschot V, Ramm G, Aui PM, Sekine Y, Deliyanti D, Wilkinson-Barka J, Niego B, Harvey AR, Theotokis P, McLean C, Strittmatter SM, Petratos S. (2019) Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis (EAE) preserves axonal transport and abrogates inflammatory demyelination. Journal of Neuroscience 39(28):5562-5580.
- Kim MJ, Kang JH, Theotokis P, Petratos S. (2018) Can We Design A Nogo Receptor-dependent Cellular Therapy to Target MS? Cells 20:8(1).
- Alrehaili AA, Lee JY, Bakhuraysah MM, Aui PM, Magee KA, Thomas S, Petratos S. (2018) The expression of Nogo Receptor homologs on activated microglia/macrophages limits the rapid clearance of myelin debris during EAE. Neural Regeneration Research 13(5):896-907.
- Mokhtar SH, Bakhuraysah MM, Aui PM, Magee KA, Alrehaili AA, Steer DL, Kenny R, McLean C, Azari MF, Birpanagos A, Petratos S. (2018) The Amyloid-beta-dependent phosphorylation of CRMP-2 dissociates kinesin in Alzheimer’s disease. Neural Regeneration Research 13(6):1066-1080.
- Tolcos M, Petratos S, Hirst JJ, Wong F, Spencer SJ, Azhan A, Emery B, Walker DW. (2017) Blocked, Delayed, or Obstructed: What Causes Poor White Matter Development in Intrauterine Growth Restricted Infants? Progress in Neurobiology 154:62-77 (5Yr IF=11.92)
- Lee JY, Li L, Velumian AA, Aui PM, Fehlings MG, McLean C, Petratos S. (2017) Nogo receptor 1 regulates axo-glial units in the central nervous system. Scientific Reports 7:8598
- Lee JY, Kim MJ, Deliyanti D, Azari MF, Rossello F, Stanley EG, Elefanty AG, Wilkinson-Berka JL, Petratos S. (2017) Overcoming monocarboxylate transporter 8 (MCT8)-deficiency to promote human oligodendrocyte differentiation and myelination. EBioMedicine 25:122-135.
- Dahl LCM, Nasa Z, Chung JY, Niego B, Tarlac V, Ho H, Galle A, Petratos S, Lee JY, Alderuccio F, Medcalf RL (2016) The influence of differentially expressed tissue-type plasminogen activator in experimental autoimmune encephalomyelitis: Implications for multiple sclerosis. PLoS ONE 11(7):e0158653.
- Lee JY & Petratos S (2016) Thyroid hormone signaling in oligodendrocytes: From extracellular transport to intracellular signal. Molecular Neurobiology 53(9):6568-6583.
- Alshehri B., D’Souza DG., Lee JY., Petratos S., Richardson SJ. (2015) The diversity of mechanisms influenced by transthyretin in neurobiology: development, disease and endocrine disruptors. Journal of Neuroendocrinology 27(5):303-323.
- Lee JY, Biemond M, Petratos S. (2015) Axonal degeneration in multiple sclerosis: defining therapeutic targets by identifying the causes of pathology. Neurodegenerative Disease Management 5(6):527-48.
- Bakhuraysah MM, Siatskas C, Petratos S. (2015) Is Hematopoietic Stem Cell Transplantation for Multiple sclerosis a clinical reality? Stem Cell Research & Therapy 7 (1): 12.
- Deliyanti D, Lee JY, Petratos S, Meyer C, Ward KW, Wilkinson-Berka JL, de Haan JB. (2015) A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates vasculopathy in mice with ischaemic retinopathy. Clinical Science 130(15):1375-87.
- Lee JY, Taghian K, Petratos S. (2014) Axonal degeneration in Multiple Sclerosis. Can we predict and overcome a permanent disability? Acta Neuropathologica Communications. 2(1):97.
- Sutinen EM, Korolainen MA, Häyrinen J, Alafuzoff I, Petratos S, Salminen A, Soininen H, Pirttilä T, Ojala JO. (2014) Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells. Frontiers in Cellular Neuroscience 8:214.
- Litwak SA, Payne NL, Campanale N, Ozturk E, Lee JY, Petratos S, Siatskas C, Bakhuraysah M, Bernard CC. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. PLoS One. 2013 5;8(12):e82101.
- Mokhtar SH, Bakhuraysah MM, Cram DS, Petratos S. (2013) The Beta-amyloid protein of Alzheimer's disease: communication breakdown by modifying the neuronal cytoskeleton. International Journal of Alzheimers Disease. 2013:e910502.
- Lee JY and Petratos S. Multiple Sclerosis: Does NOGO Play a role? The Neuroscientist (2013) 9(4):394-408.
- Petratos S and Lee JY. (2013) Stop CRMPing my style: A new competitive model of CRMP oligomerization. Journal of Neurochemistry 125(6):800-2.
- Alsanie W., Niclis J., Petratos S. (2013) Human ESC derived oligodendrocytes: Protocols and perspectives. Stem Cells and Development 22(18):2459-76.
- Petratos S., Ozturk E, Azari MF, Kenny R, Lee JY, Magee KA, Harvey AR, McDonald C, Taghian K, Moussa L, Aui PM, Siatskas C, Litwak S, Fehlings MG, Strittmatter SM, Bernard CCA (2012) Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain 135, 1794-1818.
- National Phase (PCT/AU2015/000770; #WO2016/101017A1 in the name of NeuOrphan Pty Ltd entitled: Improvements in oligodendroglial cell culturing methods and in methods for treating neurodegenerative disorders
by using thyroid hormones or analogues).
Research Support in the last 5 years (over $3 million in career):
1. National Multiple Sclerosis Society (USA) Project Grant Investigators: Dr Steven Petratos, Professor Claude Bernard, Dr Christopher Siatskas, Professor Stephen Strittmatter, Professor Alan Harvey, Professor Michael Fehlings, Dr Alexander Velumian (2011-2014) – $510,555
2. National Multiple Sclerosis Society (USA) Pilot Grant Investigators: Dr Steven Petratos (2014-2015) – $40,000
3. National Multiple Sclerosis Society (USA) Progressive MS Alliance Project Grant Investigators: Dr Steven Petratos, Professor Stephen Strittmatter, Professor Michael Fehlings (2014-2015) – Euro 75,000
4. National Multiple Sclerosis Society (USA) Pilot Grant Investigators: CIA A/Prof Samantha Richardson CIB Dr Steven Petratos (2014-2015) - $USD 40,000
5. NeuOrphan P/L Commercial Project Funding Investigators: Dr Steven Petratos (2014-2015) - $238,000
6. Multiple Sclerosis Research Australia & Trish Multiple Sclerosis Research Foundation Project Grant Investigators: Dr Steven Petratos, A/Prof Frank Alderuccio (2016-2017) - $160,000
7. Bethlehem Griffiths Research Foundation Project Grant Investigators: Dr Steven Petratos (2017) - $ 46,5038. Multiple Sclerosis Research Australia & Trish Multiple Sclerosis Research Foundation Project Grant Investigators: Dr Steven Petratos, Dr Kaylene Young (2018) - $70,000
9. Multiple Sclerosis Research Australia & Trish Multiple Sclerosis Research Foundation Pilot Grant
Investigators: Dr Steven Petratos; Dr Kaylene Young (2018) - $25,000
10. Bethlehem Griffiths Research Foundation Project GrantInvestigators: Dr Steven Petratos; Dr Kaylene Young (2019) - $ 48,956
International collaborators: Prof Stephen Strittmatter (Yale University); Prof Michael Fehlings (Uni of Toronto); Assist Prof Alexander Velumian (Uni of Toronto); Prof Nikolaos Grigoriadis (AHEPA University Hospital); Assoc Prof Speros Efthemiopoulos (Uni of Athens).
National collaborators: Prof Alan Harvey (University of Western Australia); Assoc Prof Kaylene Young (University of Tasmania); Prof Catriona McLean (Alfred Hospital); Prof Edouard Stanley (Murdoch Institute); Prof Andrew Elefanty (Murdoch Institute).
- May 2012 Channel 10 Late News, ABC News, ABC 24 NEWS; The Herald Sun; Today Tonight (“Nicole’s Story”)