Picking the ideal treatment for people with schizophrenia – new project funded in the CBR

Patients with schizophrenia could soon be prescribed tailored drugs for their biology, as a new project gets underway in the Centre for Brain Research. Funding from the Auckland Medical Research Foundation has enabled promising Research Fellow Dr Valerie Anderson to undertake the research.

Standard medications are not affective in approximately a third of people with schizophrenia, and these patients are considered ‘treatment-resistant’. Alternative medication and combinations of antipsychotics must be used, but these medications have a greater risk of inducing serious side effects and therefore are avoided where possible. Consequently, people with treatment-resistant schizophrenia often experience many years of unsuccessful therapy with standard medications before alternatives are prescribed, during which time their symptoms severely affect daily living and have a significant impact on long-term outcomes.

 The Psychopharmacology team will now investigate whether they can identify measurable biological characteristics (biomarkers) that could be used to predict whether people with schizophrenia will be treatment-resistant. Brain magnetic resonance imaging, electroencephalography, and neuropsychological data will be collected and analysed to investigate the structure and function of the brain in people with schizophrenia who are treatment-resistant, and the findings compared to people with schizophrenia who respond well to standard medications and normal subjects.

 Identification of reliable biomarkers to predict treatment-resistant schizophrenia would enable alternative medications to be prescribed earlier in the disease course. This will ultimately minimise the time that these patients experience debilitating symptoms, leading to improved outcomes for them, and reducing the burden on their families and health care providers.

 The Auckland Medical Research Foundation has also funded two new PhD scholarships at the Centre for Brain Research. Foundation Executive Director Kim McWilliams says: “Many of these researchers already have and will go on to become leaders and internationally recognised in their particular discipline or field of medicine.”

 Projects:

Biomarkers for treatment resistant schizophrenia ($179,267 – two years)
Dr Valerie Anderson, Psychopharmacology and Neurodynamics

 
 
Preterm stem cell therapy (Doctoral Scholarship $122,000 – three years)
Miss Lotte van den Heuij, Fetal Physiology

Visual brain plasticity in adult humans (Doctoral Scholarship $122,000 – three years)
Mr Victor Borges, Visual Neuroscience Group

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Promising young brain researcher returns to NZ

Hawkes Bay-born Dr Erin Cawston has been named the 2011 Neurological Foundation Repatriation Fellow. Erin will return from her position as Research Fellow at the Mayo Clinic Arizona next month, in order to further her research into Huntington’s disease at the Centre for Brain Research.

 The Repatriation Fellowship ensures outstanding young researchers who have completed postdoctoral studies overseas can return home and continue to develop their research careers in their specialist area. Dr Cawston says “I am incredibly grateful to the Neurological Foundation for this Repatriation Fellowship allowing me to come home to New Zealand. I look forward to working with Associate Professor Michelle Glass and Professor Mike Dragunow on such an exciting project as well as being back amongst the New Zealand scientific community.” Dr Cawston begins her Fellowship at The University of Auckland in February.

 Alongside this exciting research, the Neurological Foundation has also funded a number of exciting new research projects at the CBR.

 Optimising a novel induced neural precursor-like cell line Associate Professor Bronwen Connor, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research University of Auckland, $136,862 

 The generation of ‘embryonic-like’ stem cells from adult human skin was first demonstrated in 2007. This project will advance this capability by directly generating immature brain cells (neural precursor cells) from adult human skin. Of major significance is that this will avoid the need to generate an intermediate embryonic-like stem cell phase, providing neural precursor cells for therapeutic applications without risk of tumour formation from stem cells. This project provides a unique opportunity to establish a novel technology which is likely to have wide-reaching applications for future research in the areas of neurological disease modeling, drug development, and potentially cell replacement therapy.

 A genetic mechanism underlying late-onset Alzheimer’s disease Professor Russell Snell, School of Biological Sciences University of Auckland, $86,875

 Alzheimer’s disease is a debilitating disorder affecting up to 50 per cent of those aged over 80 years old. Despite decades of research and innumerable clinical trials, there are no treatments that prevent or reverse the progression of the disease. There is currently some evidence that patients have a small proportion of brain cells with three copies of chromosome 21 instead of the normal two, leading to an increased production of the toxic protein amyloid-beta peptide. This study aims to confirm this observation, determine the pathological consequences of these cells and look for markers that make these cells different, which may lead to new therapies.

 Immodulation of stroke with risperidone Associate Professor Bronwen Connor, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of Auckland, $11,999

 Stroke is a leading cause of disability in New Zealand and the burden associated with this neurological disorder is increasing. Treatment of stroke represents a large, unmet medical need. Neuroinflammation is an important pathophysiological mechanism involved in stroke and impacts profoundly on the extent of cell loss, as well as injury progression. Neuroinflammation therefore offers an exciting therapeutic target for the treatment of stroke. It has been recently demonstrated that the anti-psychotic drug, risperidone, is effective at reducing neuroinflammation and disease progression in a model of multiple sclerosis. This project will now explore whether the anti-inflammatory properties of risperidone can reduce the progression and severity of stroke. 

 Do BMP antagonists play a role in directing the fate of adult neural progenitor cells following neural cell loss?
Shwetha George, Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of Auckland, $4,000

 The ability for adult neural stem cells to migrate to areas of brain damage and generate replacement brain cells may provide a unique mechanism by which to develop novel therapeutic strategies for the treatment of brain injury or neurological disease. However, the local environment appears to be critical for directing the final fate of adult stem cells in the damaged brain. This study will investigate whether brain injury alters the expression of a group of compounds known as bone morphogenic protein antagonists to promote adult neural stem cells to form glial rather than neuronal cells. The results of this study will enhance our knowledge as to how stem cells respond to brain cell loss and may assist in the development of novel therapeutic strategies for the treatment of brain injury or disease.

Funding for innovation

Four CBR researchers have been awarded prestigious Marsden grants for innovative New Zealand research.

The Marsden Fund is regarded as a hallmark of excellence, allowing New Zealand’s best researchers to explore their ideas. It supports projects in the sciences, technology, engineering and maths, social sciences and the humanities. The fund is administered by the Royal Society of New Zealand on behalf of the government.

Associate Professor Michelle Glass was awarded $900,000 for her work on G-protein coupled receptors. This class of receptors represents the target for 50% of all drugs on the market, and Michelle aims to find a new way of altering G protein signalling.

Associate Professor Nigel Birch was awarded $895,000 for research on neuroserpin and its potential role in the human immune system. Professor Margaret Brimble was awarded $825,000 to determine the structure of proteins through racemic protein crystallography. Meanwhile evolutionary psychology research Professor Russell Gray was awarded $775,000 to use his methods of studying evolution to look at how religion has developed.

Marsden Fund Council chairman Professor Peter Hunter said he is proud to be part of the Marsden Fund system and is continually impressed at the quality of the applicants and the proposals.

“The Marsden Fund supports leading-edge research, which creates economic growth and increases our understanding of issues, from medical advancements to social change and development.

“Most breakthroughs around the world come from this basic science end of the research spectrum, which is what makes the Marsden Fund both exciting to be part of and vital for New Zealand to invest in.

“The newly funded projects from the country’s top researchers are all excellent. However, we are very aware that there were many more extremely worthy projects that we were unable to fund.”

Applications to the Marsden Fund are extremely competitive. Of the 1078 preliminary proposals received, 250 were asked to submit a full proposal with 88 ultimately funded, giving a success rate of 8.2%. All of the funded proposals are for three years.

New hope for neurological patients with Health Research Council Funding

Groundbreaking research developing new treatments for neurological disorders has been given the go-ahead with funding from the Health Research Council of New Zealand (HRC). Over $7 million of grant funding has been awarded to scientists working in the Centre for Brain Research.

The new programmes include $4.46M over five years to Professor Mike Dragunow and his team running the Biobank and Human Brain Bank. Over 100,000 New Zealanders are currently living with neurodegenerative conditions. The rate of Alzheimer’s disease is increasing in New Zealand, and CBR researchers are contributing to the global effort to find more effective treatments to combat this, and other devastating neurological disorders.

Professor Dragunow will work with Professor Richard Faull and other scientists to study the underlying causes and treatments for Alzheimer’s, epilepsy, Parkinson’s, and Huntington’s disease. The world-class team of neuroscientists and chemists has well-developed linkages with neurosurgeons, gerontologists, other clinical groups in the District Health Boards involved in clinical trials, and with NZ Biotech industries. Their goal is to translate lab-based research into therapies for patients suffering from neurodegenerative diseases.

Other projects funded include a study to determine personalized treatment pathways for stroke patients. Dr Cathy Stinear and her team at the Brain Recovery Clinic will use MRI and other techniques to define the rehabilitation strategy which will work best for each patient. In another project, Professor Laura Bennet’s team will examine whether stem cells can help brain-injured preterm babies. Meanwhile Professor Suzanne Purdy’s speech therapy team will look at therapeutic outcomes from being part of the CeleBRation Choir.

HRC New Programmes:

Professor Michael Dragunow, The University of Auckland, phone (09) 923 6403
Neurodegeneration in the Human Brain – Mechanisms and Therapeutic Targets
60 months, $4,467,504

HRC Projects:

Professor Laura Bennet, The University of Auckland, phone (09) 373 7599 ext 84890
Can Pluripotent Amnion Epithelial Cells help the Injured Preterm Brain?
36 months, $1,154,402

Professor Valery Feigin, AUT University, phone (09) 921 9166
Extension to the Traumatic Brain Injury Burden in New Zealand Study 
14 months, $345,465

Dr Cathy Stinear, The University of Auckland, phone (09) 923 3779 ext 83779
TRIO: Targeted Rehabilitation, Improved Outcomes
36 months, $1,126,268

HRC Feasibility Study Grants:

Professor Suzanne Purdy, The University of Auckland, phone (09) 373 7599 ext 82073
SPICCATO: Stroke and Parkinson’s Community Choir Engagement and Therapeutic Outcomes
12 months, $149,986

Grant funding success for CBR researchers

Scientists at the Centre for Brain Research have been awarded almost $500,000 for four new research projects. The funding comes from the Auckland Medical Research Foundation and the Neurological Foundation of New Zealand.

The studies will examine the underlying biology of brain disorders including autism and neurodegenerative disease. Potential new treatments being developed include stem cell research on induced neural precursor cells, and a clinical trials system called EpiNet.

 INDUCED NEURAL PRECURSOR CELLS ($144,023 – 2 YEARS)
Dr Bronwen Connor, Dr Christof Maucksch, Dr Mirella Dottori, A/Prof Cris Print,  Dept of Pharmacology, The University of Auckland. Funded by Auckland Medical Research Foundation.

It has long been considered that once a cell reaches maturity it is unable to change to a different cell type. However, recent advances in stem cell biology have shown that mature cells, such as skin cells, can be transformed back to an “embryonic-like” stem cell state where cells exhibit pluripotency (the ability to become any cell type) by the forced expression of specific genes (reprogramming). Advancing this capability, we propose it is possible to convert one cell type to another directly, without the need to first revert the cell to a pluripotent stem cell state. This project aims to establish an innovative approach for generating immature brain cells (neural precursor cells) directly from adult human skin. Of major significance is that this will avoid the need to generate an intermediate embryonic stem cell phase, providing neural precursor cells for research and therapeutic applications without risk of tumour formation from pluripotent stem cell contamination. This project will establish cell reprogramming as a key capability in New Zealand. The ability to directly generate human neural precursor cells offers a powerful system for studying brain development, modeling neurological disease, drug discovery and eventually, cell replacement therapy.

THE SYNAPTIC BASIS OF AUTISM ($136,351 – 1 YEAR)
Co-funded by Auckland Medical Research Foundation and the Neurological Foundation
Dr Johanna Montgomery, Prof Craig Garner, Dept of Physiology & Centre for Brain Research, The University of Auckland.

Autism Spectrum Disorders are complex disorders that are diagnosed based on behavioural symptoms including social and cognitive impairments, communication difficulties and repetitive behaviours. Interestingly, many of the genes that have been implicated in Autism encode proteins found at excitatory synapses in the brain. In this research proposal we will form an international collaborative research effort to test the hypothesis that the Autism-associated mutations in these synaptic proteins disrupt the function of synapses. Using electrophysiology recordings as a measure of synapse function, we will compare how proteins that are associated with Autism can alter synapses in the hippocampus, the part of the brain critical for cognitive functions such as learning and memory. We will also begin to determine the mechanisms underlying how these changes occur. These experiments have the potential to determine how the formation, plasticity and maturation of excitatory synapses may be disrupted in Autism, leading to interference with cognitive function and behaviour.

CB2 IN THE BRAIN ($74,457 – 1 YEAR)
Prof Michelle Glass, Dr Scott Graham, Dept of Pharmacology & Clinical Pharmacology, The University of Auckland. Funded by Auckland Medical Research Foundation.

Cannabinoid CB2 receptors have been suggested to be an appealing target for neuroinflammatory disorders as many believe them to be found only on immune cells. However, their distribution is actually highly controversial with some groups reporting wide spread neuronal distribution, while others see little evidence for CB2 in the brain. Part of the reason for these discrepancies are that the antibodies used to detect this protein are not entirely specific. Furthermore, many of the assumptions about CB2 expression in the brain are based on animal studies and may not represent the situation in the human brain. As many drug companies are aiming to bring CB2 directed therapies onto the market it is critical that the localisation of the receptor be accurately determined. This study aims to optimise a sensitive method which will allow for the determination of CB2 gene expression in the normal healthy human brain.

VALIDATION OF THE EpiNet PLATFORM AND THE EpiNet STUDY GROUP

Dr Peter Bergin, Auckland City Hospital, Auckland ($85,464)

Funded by the Neurological Foundation.

In the July 2009 grant round, the Neurological Foundation approved funding for Dr Peter Bergin’s international collaborative pilot study which set up an internet-based platform to recruit patients for epilepsy drug trials. The platform, called EpiNet, is now functioning and is able to be accessed by adult and paediatric neurologists from anywhere in the world. In this second study phase, the EpiNet study group, led by Dr Bergin and involving an international collaboration of epileptologists, will undertake a study to validate both the EpiNet study group and the EpiNet platform before undertaking clinical trials. The group will circulate 50 fictitious case histories to doctors who have expressed interest in participating in the EpiNet project, and ask them to enter details into the EpiNet database, using standard and internationally approved epilepsy classification systems. Investigators’ results will be compared. As well as confirming that investigators ‘speak the same language’ globally, the study will also determine how much variability there is when classifying individual cases using the classification schemes. At the same time, the group will undertake steps to confirm that the database and systems procedures are robust.