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motor neurone disease and neurotrophic research laboratory

MND, biomarkers, targeted gene therapies...

Visit with MND Australia and Lab Staff

Research Summary

*Formerly called the Neurotrophic Laboratory - changed in 2015, to reflect a change of headship and direction (from E.Prof Rush to Dr Rogers).

A major focus of our research is biomarkers and targeted treatments for the devastating Motor Neuron Disease (MND, also known as Amyotrophic Lateral Sclerosis (ALS).

There is an urgent need for a validated biomarker for MND that also tracks disease progression, especially in clinical trials of potential therapies, as there are none for MND. We are also refining a targeted non-viral gene delivery method that could be used to deliver treatments for MND, specifically firstly in MND mice. Neurons require unique proteins called neurotrophic factors that need receptors to enter neurons and produce their effect. We have been focusing on the common neurotrophin receptor p75 (p75NTR) that binds Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin 3 (NT3) and 4 (NT4) and their pro-neurotrophin forms. p75NTR is highly expressed in motor neurons during development, down-regulated in adulthood and re-expressed when motor neurons are injured, including MND. We have been focused on utilising this knowledge to develop biomarkers of disease progression based on the cleavage of the extracellular domain from injured motor neurons. In addition we are developing a way of targeting gene therapy called immunogenes to motor neurons expressing p75NTR and to the TrkC receptors. Therefore, our research has potential to change outcomes, especially in the development of effective therapies.

 

 

You can now donate directly to the work of the MND & Neurotrophic Research Laboratory, through the Flinders Medical Centre Foundation: http://teamflinders.com.au/motorneurondiseaseresearchfund/default.aspx

 

Research Projects

An important step in finding effective treatments for MND is to identify biomarkers that assess the effectiveness of potential therapies that could improve outcomes for this devastating disease. Urine is an easily obtained biomarker source compared to cerebral spinal fluid (CSF) and has a simple proteomic profile when compared to blood. We have found by immunoprecipitation/western blot (IP/WB) that the extracellular domain of p75NTR (p75ECD) is present in urine of MND patients and in urine from the mouse model of MND (SOD1G93A mice). This is compared to low to undetectable amounts in healthy controls and in control mice. We have developed quantitative sandwich ELISAs to detect mouse and human p75ECD in the ρg/ml range, and shown significant urinary p75ECD is present in people living with MND compared to healthy control and those living with other neurological diseases (Shepheard et al., 2014).
In further analysis, we analysed urinary p75ECD in n=23 healthy controls and n=54 people with MND, in 31 of whom longitudinal samples were acquired. Confirming our previous findings, p75ECD was significantly higher in MND patients (5.6 ± 2.3 ng/mg creatinine) compared to controls (2.6 ± 0.96ng/mg, p<0.0001).
Urinary p75ECD correlated strongly with function shown by ALS functional rating scale (ALSFRS-R (r=-0.36, p<0.0001)) and increased significantly as disease progressed, at an average rate of 0.19ng/mg creatinine per month (p< 0.0001). In multivariate prognostic analysis, bulbar onset (hazard ratio (HR)=2.99, p=0.0035), change in ALSFRS (∆FRS,  ;\HR=4.3, p<0.0001), and baseline p75ECD (HR=1.31, p=0.0004) were significant predictors of survival. We are now following p75ECD levels in a sample of people from the USA with genetic risk of ALS/MND before and after symptom onset.

Currently, there is only one approved treatment for Motor Neuron Disease, Riluzole, which on average only extends the life of a patient by a few months. We are developing a receptor specific, non-viral gene delivery method called 'immunogenes' that can specifically target motor neurons, bypass the blood brain barrier and deliver therapeutic agents to motor neurons. It is well established that the common neurotrophic receptor p75NTR is highly expressed in motor neurons during embryonic development, but is down regulated once the nervous system has fully developed. Nevertheless, during injury and MND, motor neurons re-express p75NTR. Our laboratory has used antibodies to p75NTR (MLR2) to create receptor specific, non-viral gene delivery vehicles providing a way to deliver therapeutic agents for motor neuron disease in-vivo. We have now shown it is possible to target motor neurons in neonatal mice using retrograde transport to motor neurons after intraperitoneal injections of our MLR2 immunogenes. Utilising this method we demonstrated we can target 25.4% of lumbar, 18.3% of thoracic and 17.0% of cervical motor neurons in neonatal mice after peritoneal injections of the immunogene (Rogers et al., 2014). Further work will be done to improve the efficiency of this method.
In examining how we can deliver therapeutic genes to SOD1G93A (MND) mice, p75NTR re-expression was examined (Smith et al., 2015). We found p75NTR is detectable from 80days in a small population of large motor neurons that represent 5% of total motor neurons. Furthermore, p75NTR re-expression occurs in larger alpha motor neurons that express cleaved caspsase-3 and are destined to die. Hence our immunogenes using MLR2 may be more useful in neonatal mice that have diseases such as spinal muscular atrophy (SMA) than in MND. We are also examining other antibodies to receptors present on motor neurons – such as TrkC as targets for our gene delivery mechanisms.

Selected Publications

Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T, Schultz D, Benatar M, Rogers ML (2017) Urinary p75ECD: A prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology, 88(12):1137-1143

 

Brahimi F, Maira M, Barcelona PF, Galan A, Aboulkassim T, Teske K, Rogers ML, Bertram L, Wang J, Yousefi M, Rush R, Fabian M, Cashman N, Saragovi HU (2016) The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS. PLoS ONE, PONE-D-16-12238

 

Matusica D, Alfonsi F, Turner BJ, Butler TJ, R Shepheard SR, Rogers ML, Skeldal S, Underwood CK, Mangelsdorf M, Coulson EJ (2016) Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment. Journal of Cell Science, 129(3):517-30

 

Delalat B, Sheppard V, Rasi Ghaemi S, Rao S, Prestidge C, McPhee G, Rogers ML, Donoghue J, Johns T, Kröger K, Voelcker NH (2015) Targeted drug delivery using genetically engineered diatom biosilica. Nature Communications, 6:8791

 

Alba S, Delalat B, Formentin P, Rogers ML, Marsal LF, Voelcker NH (2015) Silica Nanopills for Targeted Anticancer Drug Delivery. Small, 11(36):4626-31

 

Smith KS, Rush RA, Rogers ML (2015) Characterization and changes in neurotrophin receptor p75N-expressing motor neurons in SOD1(G93A) G1H mice. Journal of Comparative Neurology, 523(11):1664-1682

 

Alhmoud H, Delalat B, Elnathan R, Cifuentes-Rius A, Chaix A, Rogers M-L, Durand J-O, Voelcker NH (2015) Porous Silicon Nanodiscs for Targeted Drug Delivery. Advanced Functional Materials, 25(7):1137-1145

 

Rogers M-L, Smith KS, Matusica D, Fenech M, Hoffman L, Rush RA, and Voelcker NH (2014) Non-viral gene therapy that targets motor neurons in vivo. Frontiers in Molecular Neuroscience, 7:80

 

Smolny M, Rogers ML (equal first author), Shafton A, Rush RA, Stebbing MJ (2014) Development of non-viral vehicles for targeted gene transfer into microglia via the integrin receptor CD11b. Frontiers in Molecular Neuroscience 7:79

 

Shepheard S, Chataway T, Schultz D, Rush RA. Rogers ML (2014) The Extracellular Domain of Neurotrophin Receptor p75 As a Candidate Biomarker For ALS. PLOS One, e87398

 

Rogers M-L (2014) Neurotrophic therapy for motorneuron disease. In Handbook of Neurotoxicity (ed R Kostrzewa, T Archer, J Segura-Aguilar, G Guillemin, X-F Zhou and D Quinones). Springer Publishing, London, ISBN 978-1-4614-5835-7

 

Secret E, Smith K, Dubljevic V, Moore E, Macardle P, Delalat B, Rogers M-L, Johns T-G, Durand J-O, Cunin F, Voelcker NH (2013) Antibody-Functionalized Porous Silicon Nanoparticles for Vectorization of Hydrophobic Drugs. Advanced Healthcare Materials, 2(5): 718-727

 

Rogers ML, and Rush RA (2012) Non-viral gene therapy for neurological diseases, with an emphasis on targeted gene delivery. Journal of Controlled Release, 157:183-189

 

Wiese S, Herrmann T, Drepper C, Jablonka S, Funk N, Klausmeyer A, Rogers ML, Rush R, and Sendtner M (2010) Isolation and enrichment of embryonic mouse motoneurons from the lumbar spinal cord of individual mouse embryos. Nature Protocols, 5: 31-38

 

Rogers ML, Bailey S, Matusica D, Nicholson I, Muyderman H, Pagadala PC, Neet KE, Zola H, Macardle P, Rush RA (2010) ProNGF mediates death of Natural Killer cells through activation of the p75NTR-sortilin complex. Journal of Neuroimmunology, 226: 93-103

 

Muyderman H, Hutson PG, Matusica D, Rogers ML, Rush RA (2009) The Human G93A-Superoxide Dismutase-1 Mutation, Mitochondrial Glutathione and Apoptotic Cell Death. Neurochemistry Research, 34:1847-1856

 

Rogers ML, Beare A, Zola H, Rush RA (2008) CD 271 (p75 neurotrophin receptor). Journal of Biological Regulators and Homeostatic Agents, 22:1-6

 

Matusica D, Fenech, MP, Rogers ML, Rush RA (2008) Characterization and use of the NSC-34 cell line for study of neurotrophin receptor trafficking. Journal of Neuroscience Research, 86:553-565

 

Skinner SJM, Geaney MS, Rush RA, Rogers ML, Emerich DF, Thanos CG, Vasconcellos AV, Tan PLJ and Elliot RB (2006) Choroid plexus transplants in the treatment of brain diseases. Xenotransplantation, 13(4):284-288

 

Rogers ML, Atmosukarto I, Berhanu DA, Matusica D, Macardle P, Rush RA (2006) Functional Monoclonal Antibodies to p75 Neurotrophin Receptor Raised in Knockout Mice. Journal of Neuroscience Methods, 158(1):109-120

 

Investigators

  • Mary-Louise Rogers, PhD

    Roshan Vasani, PhD

Support Staff

  • Michell Cardoso, Research Assistant

    Vyoma Modi, Research Assistant

Students

  • Lauren Jones, PhD Student


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