A novel approach to reduce the impact of progressive MS
Dr Steven Petratos was the only Australian researcher to receive funding from the International Progressive MS Alliance in their inaugural round of funding. The Trish Foundation has been funding a continuation of this work.
· * The progressive phase of MS results from damage to the nerve fibre than the direct inflammatory attack on myelin. It is believed that this destruction is what leads to permanent and increasing disability in progressive MS.
· * Dr Petratos’s research has investigated specific molecules that cause this damage and attempts to find ways to block the damage pathway and repair nerve fibres.
· * In his project, Dr Petratos demonstrated that one of the molecules, NgRI was key to nerve fibre damage and showed that this molecule could be blocked in a model of MS. Using a highly novel technique, he was able to deliver the blocking directly to sites of damage and repair the nerve fibre.
· * If this system could be used in people with MS, damage to the nerve fibre could be limited and lead to improvements in clinical outcomes for people with progressive MS.
The progressive phase of MS is thought to result from ongoing damage to the nerve fibre rather than the direct inflammatory attack on myelin. It is believed that destruction of the nerve fibres leads to permanent and increasing disability in progressive MS. Dr Petratos has been working on determining which molecules are responsible for this nerve fibre damage so that we can potentially stop it. In this project grant from MS Research Australia, fully supported by the Trish MS Research Foundation, Dr Petratos’ team investigated a molecule known as NgR1 and attempt to block its activity in nerve cells.
Using a laboratory model of MS, Dr Petratos’s group have identified a number of molecules that respond to the immune system damage, leading to a destructive cascade in the nerve fibres in the brain and spinal cord. If they can stop this cascade from being triggered they could potentially prevent the progressive damage in MS. In this project grant from MS Research Australia, fully supported by the Trish MS Research Foundation, Dr Petratos’ team will investigate a molecule known as NgR1 and attempt to block its activity in in nerve cells. The blocking agent of NgRI will be delivered using a highly novel method that will allow accurate targeting of the NgR1 receptor.
Dr Petratos and his team are interested in specific molecules that are part of the molecular cascade that causes nerve fibre damage in MS. During this project, Dr Petratos demonstrated that one of the molecules, NgRI was key to nerve fibre damage and that damage was caused by NgRI interrupting molecular transport along the nerve fibres. By blocking NgRI, Dr Petratos showed that the transport of molecules along the nerve fibre was restored and that this reduced the amount of nerve fibre damage and symptoms seen in the MS-like illness in the mice.
The second part of this study involved the use of some highly novel and challenging techniques to allow the delivery of a therapeutic protein to sites of damage in a laboratory model of MS. This delivery system is based on immune cells in the blood and means that the therapeutic protein can work directly on the areas of damage. Dr Petratos and his team were able to demonstrate delivery of the therapy at the height of MS symptoms in a laboratory model of MS. Excitingly, the therapy was able to reduce the symptoms of the MS-like disease and the nerve fibres were able to regrow and myelin damage was repaired.
It is hoped that if a similar system could be used in humans, it may be possible to limit the destruction which occurs to nerve fibres in the brain and spinal cord, giving a better clinical outcome for people with MS.
This grant has enabled the group to obtain funding from the Bethlehem Griffiths Research Foundation, submit three PhD, one Masters and two honours theses and build capacity for MS research.
Bakhuraysah MM, Siatskas C, Petratos S. (2016) Is hematopoietic stem cell transplantation for multiple sclerosis a clinical reality? Stem Cell Research & Therapy 7(1):12.
Dahl LCM, Nasa Z, Chung JY, Niego B, Tarlac V, Ho H, Galle A, Petratos S, Lee JY, AlderuccioF, 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.
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
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.
Alrehaili AA, Lee JY, Bakhuraysah MM, Kim MJ, Aui P-M, Petratos S. Nogo receptor expression in Microglia/Macrophages during EAE progression. Neural Regeneration Research 2018
Mokhtar SH, Bakhuraysah MM, Aui P-M, 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 2018
Lee JY, Kim MJ, Thomas S, Aui P-M, Harvey AR, Strittmatter SM, Petratos S. Targeting neuronal nogo receptor 1 (NgR1) signaling in experimental autoimmune encephalomyelitis (EAE) preserves axonal transport and limits demyelination. Acta Neuropathologica 2018 In preparation
Bakhuraysah MM, Lee JY, Alrehaili AA, Aui P-M, Kim MJ, Figgett WA, Mackay F, Siatskas C, Biemond M, Alderuccio F, Steven Petratos. BAFF stimulates Nogo receptor 3 expressing B cells prevalent at the induction of experimental autoimmune encephalomyelitis (EAE) prior to axonal damage and demyelination. Acta Neuropathologica 2018 In preparation
Kim MJ, Lee JY, Kang JH, Bakhuraysah MM, Alrehaili AA, Thomas S, Aui PM, Siatskas C, Alderuccio F, Biemond M Harvey AR, Strittmatter SM, Petratos S. Targeting neuronal nogo receptor 1 (NgR1) signaling in experimental autoimmune encephalomyelitis (EAE) preserves axonal transport and limits demyelination. Nature Medicine 2018 In preparation