INDUSTRY PARTNERSHIP FOR DEVELOPMENT OF DRUG TO REDUCE BRAIN INJURY IN STROKE AND TRAUMA

 

Project members

Scientia Professor Gary Housley

Professor

T:  +61 2 9385 1057

E:  g.housley@unsw.edu.au

 

Mr James Bonnar

CEO, Norbio No. 1 Pty Ltd

 

Project description

In stroke and traumatic brain injury (TBI), ischemia leads to rapid cell death and a prodigious expansion of the injury develops in the days following (the potential treatment window). The expansion of the brain injury is a large factor in the death and morbidity linked to stroke and TBI. Current treatments do not address this secondary wave of cell death. Original research out of the TNF showed that this secondary wave of death signalling in brain cells (neurons and glia) arises in large measure from entry of calcium ions (Ca²⁺) through ion channels coupled to G protein-coupled receptors (GPCR) that are tonically activated by dysregulated release of neurochemicals stemming from the initial brain injury (Kim et al.  J. Neurosci. 2012; Housley et al. 2018 Au Patent No. 2013286815). The opportunity to target this mechanism to treat brain injury was seized, via collaboration with the Australian biotech company Norbio No 1 (Nyrada Inc.  www.nyrada.com). Using a novel in vitro cell-based Ca²⁺ reporter assay developed in the TNF, a drug screen identified a promising stem compound that inhibited this GPCR-coupled Ca²⁺ entry brain injury mechanism. Current research at the TNF is providing critical evaluation of Norbio’s lead compound development, extending this to evaluation of neuroprotection in a preclinical stroke model (Nagarajesh et al. Translational Stroke Research 2018).  The collaborative research reflects significant progress towards an effective treatment for brain injury, that suppresses toxic calcium ion loading in brain cells following stroke and trauma, improving survivability and functional recovery. Norbio is seeking to advance the drug development through optimization steps so that it is poised for an Australia-based phase I clinical trial.

 

 

BIONIC ARRAY-BASED GENE ELECTROTRANSFER (BADGE®)

 

Project members

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  g.housley@unsw.edu.au

 

Project supporters

Australian Research Council - Linkage Project|LP0992098

 

Project description

BaDGE® gene augmentation to improve the ‘Bionic Ear’: We are working to improve hearing and speech outcomes for cochlear implant recipients. Underpinning the BaDGE® gene augmentation platform technology which is migrating to a first-in-human clinical trial to regenerate the cochlear nerve and ‘close the neural gap’ with cochlear implants.    This work is supported by the CINGT program and includes co-investigators from the UNSW Biomedical Engineering Institute, the Bionics Institute (U. Melbourne), Dept. Otolaryngology U. Sydney, Sydney Cochlear Implant Centre, Macquarie University Hearing Hub and industry partner Cochlear Ltd.

 

 

HEARING PROTECTION CONFERRED BY P2X2 RECEPTOR SIGNALING IN THE COCHLEA

 

Project members

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  g.housley@unsw.edu.au

 

Project supporters

National Health & Medical Research Council - Project Grant|APP630618

 

PHYSIOLOGICAL SIGNIFICANCE OF TRANSIENT RECEPTOR POTENTIAL (TRPC3) ION CHANNELS IN THE COCHLEA

 

Project members

Scientia Professor Gary Housley
ProfessorT:  +61 2 9385 1057
E:  g.housley@unsw.edu.au

 

Project supporters

Australian Research Council - Discovery Project|DP1097202

Project description

The transient receptor potential (TRPC3) ion channels provide Na⁺ and Ca²⁺ entry and are expressed in the cochlear hair cells and spiral ganglion neurons. A TRPC3 knockout mouse model will be used to test our hypotheses: (1) That loss of TRPC3 channel expression affects hearing function. (2) That TPC channels contribute to synaptic remodelling arising from noise exposure. (3) That TRPC3 Ca²⁺ entry channels contribute to cochlear hair cell Ca²⁺ homeostasis and regulation of membrane excitability. (4) That expression of TRPC3 channels by the spiral ganglion neurons is coupled to metabotropic glutamate receptor (mGluR) signaling and affects auditory nerve firing. (5) TRPC3 expression affects cochlear neural development.

 

CHARACTERISING AUDITORY NEURONS WITH A SUIDCIDE REPORTER TRANSGENIC MOUSE MODEL 

 

Project members

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  g.housley@unsw.edu.au

 

Dr Jeremy Pinyon
Postdoctoral Fellow

T:  +61 2 9385 1057
E:  j.pinyon@unsw.edu.au

 

Lily Pearson
PhD Student

T:  +61 2 9385 1057
E:  lily.pearson@student.unsw.edu.au

 

Project description

This project developed a transgenic mouse model that uses a peripherin promotor to drive cell type-specific expression of a fluorescent reporter and a conditional suicide element. Peripherin is a cytoskeletal protein involved in neuronal outgrowth and is only expressed in discrete populations of neurons. These populations can be visualised through the mCherry fluorescent reporter element of the transgene, which is shown in red in these images. The gene encoding the human Diptheria Toxin Receptor is also expressed in these neurons. The application of Diptheria Toxin will result in the ablation (death) of the expressing cells. By comparing hearing testing results before and after the ablation, we can understand the functional role of this population. Linking genetic differences to population function is crucial for progressing our understanding of hearing loss and how it can be treated.

 

RECREATING THE HEARING EAR  

 

Project members

Dr. Georg von Jonquieres

Postdoctoral Fellow

E: g.jonquieres@unsw.edu.au

 

Yahdiel Abihu

Honours student

 

Project description

This exciting project aspires to a novel method for restoring biological hearing. Hearing itself is fundamental to quality of life, wellbeing, and health; sensorineural hearing loss, affecting 6% of the world’s population, is among the most prevalent disabilities. It has many causes, but all involve a loss of a special process called mechano-electrical transduction or MET for short. In the hearing ear, effective MET requires the cooperative function of three cochlear elements. The basilar membrane separates sound vibrations based on pitch and transmits these vibrations to specialised hair cells sitting atop the membrane; this vibration causes mechanosensitive ion channels in the hair cells to open, causing a voltage change which is then communicated to synapsing auditory neurons via neurotransmitter release. In sensorineural hearing loss, it is these hair cells or their synapses which are dysfunctional, causing die-back of the auditory neuron dendrites. The vibration of the basilar membrane, and the cell-bodies of the auditory neurons, however, remain intact. This fact, combined with a new technology enabling controlled regrowth of the auditory dendrites onto the basilar membrane, suggests opportunity for a novel treatment method. It may be possible to use gene therapy to express mechanosensitive ion channels within the regrown auditory neurons, creating a MET apparatus like that of insects, thus restoring sound-borne hearing. While similar approaches have shown promising results in restoring vision to blind mice¹, no published literature assesses efficacy of this biomimetic gene augmentation therapy in the hearing domain. This project aims to test the hypothesis: auditory neurons can be made directly mechanosensitive. By using two gene delivery methods – both the TNF patented BaDGE technology and a viral vector, mouse auditory neuron cultures will be made to express one of several mechanotransducer proteins, ELKIN1, TMC1 or PIEZO2, along with a green-fluorescent Ca²⁺ sensor to indicate mechanosensitive action potentials. It is hoped that this will provide good preliminary data on the effectiveness of this approach to inform future directions in the battle against sensorineural hearing loss.

 

The TNF CNS Gene Therapy Group is interested in the molecular mechanisms of normal and pathological functions of neurons and myelin-forming cells in the central nervous system. Our main focus is on a group of neurological disorders termed leukodystrophies. The word leukodystrophy is of Greek origin and translates into ‘leuko = white’, ‘dys = abnormal’ and ‘troph = growth’. Leukodystrophies are genetic diseases of the brain white matter associated with an early onset and substantial mortality in children. The population incidence is estimated to be one in 7,600 live births and to date there are no effective treatments available. Our aim is to establish gene therapy protocols for leukodystrophies and related neurological disorders.

 

The first step in understanding these devastating conditions is to establish accurate, rodent disease models, which enable us to study the underlying pathophysiology and to explore novel therapeutic approaches. Once established, we leverage these models to develop novel gene therapy strategies. We have a long-standing interest in adeno-associated virus (AAV) as gene therapy vectors and as tools in basic research.

We are developing the current AAV platform in two directions:

(i) to achieve widespread and stable gene expression in the CNS following intracranial or systemic delivery; and

(ii) to overcome the inherent neurotropism of AAV for targeting specific CNS cell populations including glia.

Our research group employs state-of-the-art techniques, including behavioural testing, neurogenetics, molecular biology, histology and neuroimaging to characterise disease models and to assess the therapeutic outcome of gene therapy.

 

Project members

Dr Dominik Frohlich
CNS Gene Therapy Group Co-Lead
E: d.frohlich@unsw.edu.au

 

Adj. Professor Mattias Klugmann
CNS Gene Therapy Group Co-Lead
E:  m.klugmann@unsw.edu.au

 

Ms. Elizabeth Kalotay
Research Assistant and future PhD student
E:  e.kalotay@unsw.edu.au

 

Project supporters

NSW Office for Science and Medical Research - NSW Life Sciences Research Award

 

 

The principal aim of our research is to understand the relationship between the nervous system and the immune system, with particular emphasis on how immune cells and their mediators affect neuropathic pain, and to assess immunotherapeutic approaches. This knowledge can then be used for identifying target molecules or cells for therapeutic purposes in reducing chronic pain.

 

We use in vitro and in vivo models of neuropathic pain to investigate the neuroimmune crosstalk in the injured nervous system. Animal models include peripheral nerve injury, chemotherapy-induced peripheral neuropathy, and an autoimmune disease of the central nervous system (experimental autoimmune encephalomyelitis, EAE; a model of multiple sclerosis). In vitro models include primary cultures of dorsal root ganglia sensory neurons, microglia and regulatory T cells. 

 

Projects related to this group

 

TARGETS AND MECHANISMS IN REDUCING NEUROPATHIC PAIN THROUGH IMMUNOMODULATORY TREATMENTS

 

Project members

Associate Professor Gila Moalem-Taylor
Associate Professor

T:  +61 2 9385 2478
E:  gila@unsw.edu.au

 

Project supporters

National Health & Medical Research Council - Project Grant| APP1162060

 

Project description

Inflammation in the central nervous system has been implicated in neuropathic pain, a debilitating chronic condition that imposes a huge economic and social burden. This project will investigate the effects of immunotherapeutic approaches, using spinal delivery of regulatory T cells and their novel anti-inflammatory mediator interleukin-35, on the molecular signature of CNS immune cells (microglia) and on the profile of immune responses in CNS boundaries using pre-clinical models of neuropathic pain due to nervous system injury or disease.

 

INVESTIGATING NEUROPROTECTIVE STRATEGIES IN CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

 

Project members

Associate Professor Gila Moalem-Taylor
Associate Professor

T:  +61 2 9385 2478
E:  gila@unsw.edu.au

 

Project supporters

Cancer Institute of NSW - CINSW 14/TPG/1-05 grant

 

Project description

At present, there are no effective treatments for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) and its progression. Thus, identifying neuroprotective strategies is a key priority for maintaining chemotherapy treatments and preventing neurological toxicities. Our research team has developed both in vitro and in vivo pre-clinical models of CIPN, which enable testing the effects of neuroprotective candidates on chemotherapy-induced neurotoxicity. These models include cultured dissociated sensory neurons isolated from dorsal root ganglia (DRG) of mice, and whole DRG explants (3D culture) with preserved microenvironment and intact cellular network. Treatment with the chemotherapeutic drugs oxaliplatin, a platinum-based intercalating agent, or paclitaxel, an anti-tubulin drug causes neurotoxicity, which is manifested by inhibition of neurite outgrowth and increased neuronal excitability. For in vivo studies, we developed physiologically relevant mouse models of oxaliplatin- and paclitaxel-induced peripheral neuropathy demonstrating quantifiable behavioural deficits, neuropathic pain symptoms, and nervous system damage. These models enable us to comprehensively assess the effects of novel compounds and identify the underlying mechanisms of their potential neuroprotective effects for the treatment of CIPN.

 

IMMUNOMODULATION OF NEUROPATHIC PAIN IN MULTIPLE SCLEROSIS

 

Project members

Associate Professor Gila Moalem-Taylor
Associate Professor

T:  +61 2 9385 2478
E:  gila@unsw.edu.au

 

Project description

The aims of this research are to assess the effects of immune modulation by inducing immune tolerance and manipulating regulatory T cells on pain behaviours in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This study promises to significantly enhance our understanding of the immunological mechanisms underlying neuropathic pain in MS and thereby offers hope for new approaches to therapeutic intervention.

 

 

IONIC DIRECT CURRENT FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN 

 

Project members

Associate Professor Gila Moalem-Taylor
Associate Professor

T:  +61 2 9385 2478
E:  gila@unsw.edu.au

 

Dr. Felix Peter Aplin

Post-doctoral Fellow

E: f.aplin@unsw.edu.au

 

Project description

Electrical neuromodulation using neural implants is an increasingly popular therapy for chronic pain management, with several key advantages over traditional pharmaceutical approaches. A new type of neural modulation approach, ionic direct current (iDC), dampens or blocks the responses of hyperexcitable pain fibers. This project investigates the potential of iDC to treat pain in pre-clinical models of neuropathic pain, as well as its suitability for chronic implantation and stimulation, using a combination of nerve recordings (electrophysiology), behaviour, histology, and biomedical engineering.

 

Project supporters

National Health & Medical Research Council - Project Grant| APP1187416

 

One aspect of the research conducted in the Neurosystems Group is to use viral-mediated gene therapy to modulate the levels of neurotrophins and other therapeutic molecules into the injured spinal cord with the aim of promoting axonal regeneration and the recovery of motor function.  An emerging theme within the Neurosystems Group is to characterise the effects of such deafferentation on these motor neurons. Methods of investigation include immunohistochemistry, western blotting and ELISA, RT-PCR and nerve excitability techniques. Another facet of the research in the Neurosystems Group is to investigate the neural basis of skilled reaching. Rats are trained to reach for sugar pellets, a paradigm called the "Single Pellet Skilled Reaching Task" after which they are subjected to different lesions of the brain and spinal cord that are known to be involved in motor control. The main objective is to characterise the exact contribution of these structures to fine motor control of the forelimb and the paw.

 

Projects related to this group

 

MODULATION OF BDNF EXPRESSION IN MOTOR NEURONS TO PROMOTE RECOVERY OF HAND/DIGITS MOTOR FUNCTIONS IN A RAT MODEL OF RUBROSPINAL TRACT INJURY

 

Project members

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  renee.morris@unsw.edu.au

 

Project supporters

Christopher and Dana Reeve Foundation (USA) - Individual Research Grant

 

DELIVERY OF BDNF TO MOTOR NEURONS TO PROMOTE AXONAL REGENERATION AND RECOVERY OF MOTOR FUNCTION

 

Project members

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  renee.morris@unsw.edu.au

 

Adjunct Professor Matthias Klugmann
Adjunct Associate Professor

T:  +61 2 9385 1056
E:  m.klugmann@unsw.edu.au

 

Project supporters

Brain Foundation - Research Grant

Project contacts

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  renee.morris@unsw.edu.au

 

 

The focus of our research is to “close the loop” on sensorimotor control. We use a combination of electrophysiology, signal processing and machine learning in small animal models to discover how sensory information is coded in different parts of the central nervous system. We are looking at certain brain regions for the potential to replaced lost sensory information with electrical inputs from a prosthetic device (neuroprosthesis).

 

Projects related to this group

 

BIONIC TOUCH

We are investigating the potential for the DCN as a somatosensory neuroprosthetic target. This project decodes sensory signals in the DCN in response to peripheral stimuli to predict the location and quality of sensory input. We will also stimulate the DCN to “recreate” the same electrical signatures evoked by natural stimuli.

 

DCN ACTIVITY MAPPING

DCN activity is not symmetrically mapped across the surface of the brainstem. This project investigates the asymmetry of sensory representation in the context of handedness.

 

SPINAL CORD PRE-PROCESSING OF SOMATOSENSATION

Sensory information may be significantly modified between the periphery and the DCN. This project focuses on the influence the spinal cord has on modulating ascending sensory inputs to the DCN.

 

RED LIGHT THERAPY IN NEURONAL INJURY

Another interest of our group is how the somatosensory and motor systems are affected by injury. This project investigates the use of red-light therapy for treating the nervous system in response to injury.

 

PAIN AND TOUCH PROCESSING  

How can we manipulate the brain and spinal cord to turn down unwanted pain, but without affecting touch and proprioception? We apply several approaches, which include the use of new nanomedicines and sophisticated electrical neuromodulation techniques to isolate pain pathways from other important somatosensory modalities.

 

Project contacts

Dr Jason Potas
Senior Lecturer

T:  02 9385 0017

E:  j.potas@unsw.edu.au

 

 

Our group investigates the cellular mechanisms of memory formation. We aim to identify novel mechanisms that modulate or preserve neuronal connections. This may be translated into treatments for disorders of impaired or aberrant connectivity, such as addiction, Alzheimer’s disease, stroke, PTSD, and epilepsy.

 

Projects related to this group

 

ADDICTION ASSOCIATED NEURAL PLASTICITY

Drugs of abuse cause superphysiological activation of brain pathways involved in processing natural and drug rewards, overwhelming the homeostatic mechanisms that normally constrain reward-associated behaviours and neuronal plasticity.

 

THE ROLE OF ENDOPLASMIC RETICULUM IN NEURONAL CALCIUM SIGNALING

Memory and plasticity are governed by Ca²⁺. The endoplasmic reticulum (ER) is the primary regulatory organelle for Ca²⁺signalling. We have shown that metabotropic receptor stimulation releases Ca²⁺ from the ER generating wave-like rises in dendritic calcium that invade the nucleus and a subset of spines. Using genetically encoded Ca²⁺ sensors to we are evaluating the ER’s capacity to integrate Ca²⁺over space and time.

 

Project Contacts

Dr John Power
Senior Lecturer

T:  +61 2 9385 2910

E:  john.power@unsw.edu.au