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  Areas of Excellence Scheme Project: Achievement Summary of The Institute
of Molecular Technology for Drug Discovery and Synthesis

  Areas of Excellence Scheme Project: Molecular Neuroscience: Basic
Research and Drug Discovery

As the proportion of the world’s elderly population increases, the number of people afflicted with brain diseases is similarly increasing since most of these are age-related conditions. Age-related brain diseases such as Alzheimer’s disease and Parkinson’s disease already represent a leading cause of mortality in the elderly with enormous social burden, but despite their rising incidence, there are few approved drugs in the market to effectively cure these ailments. In some cases, they are not effective in all patients or exhibit sideeffects, while in other cases, they merely alleviate the symptoms of the disease. Hence, the development of effective therapeutic drugs to treat diseases of the brain is of paramount importance.

The main obstacle towards developing treatments for brain diseases is the lack of a clear understanding of the disease. The complex and delicate biological processes within both the normal and diseased brain must be understood at a molecular level, and specific molecular targets linked to different disease states have to be identified. As a means to address this, in 2001, a cross-institutional research project led by the Hong Kong University of Science and Technology (HKUST) was allocated HK$26.8 million from the University Grants Committee (UGC) Areas of Excellence (AoE) Scheme to conduct a five-year project on “Molecular Neuroscience: Basic Research and Drug Discovery”.

The aim of this AoE project was to advance the frontiers of neuroscience research, and develop new strategies and tools towards the goal of developing novel therapeutic treatments for brain diseases. A highly-talented multi-disciplinary team with proven strengths in leading-edge research was amassed, cutting-edge research was undertaken, and a unique drug development approach based on Traditional Chinese Medicine (TCM) was established. Novel TCM-derived drug candidates as potential treatments for brain
-related ailments were subsequently identified. Upon reassessment in 2007, UGC commended the project as “an impressive programme with exceptional performance” and provided the team with additional funding of HK$27.5 million for another three years. With this sustained funding, the team examined the complex processes within the brain and explored the mechanisms underlying specific neuro-related diseases. The TCM-derived novel compounds were further developed towards clinical applications, while potential strategic partners for their downstream commercial development were identified.

Establishing Research Excellence
The team has established a unique knowledge-based drug-discovery strategy whereby TCM herbs are used as the source for potential drug candidates to treat neurological diseases. A world-class research infrastructure has been developed which includes best-in
-class facilities for TCM herb fractionation and cell-based high throughput drug screening. A large collection of herbs has been amassed and correlated with specific neurological activities based on centuries of documentation to facilitate herb selection, while the process of effectively isolating biologically active compounds from TCM herbs has been developed and optimized. A variety of drug screening tools and novel methodologies have also been developed to support the research activities. To facilitate the identification of active herb components, a vast array of proprietary screening platforms has been established, and to facilitate drug screening, a large collection of molecular targets associated with neurological diseases have been identified. Other proprietary methodologies and animal models have also been developed
and established.

The team’s particular strengths in molecular and cellular mechanisms have resulted in numerous breakthroughs within the field. These include understanding the manner in which neural cells communicate with each other, unveiling previously unknown mechanisms that drive specific biological activities in normal and disease brains, identifying the key proteins and molecular targets that play major roles in neurodegenerative diseases, and developing drug leads for treating brain-related ailments. All of these have major implications in brain research and the future development of therapeutics for brain diseases. For instance, the AoE team has identified a novel role of a cell surface protein EphA4 in the regulation of brain plasticity, a phenomenon underlying our cognitive functions by allowing nerve cells to adjust their functional efficacy based on experience. Since many neurodegenerative diseases are associated with impaired neurotransmission, these findings highlight EphA4 as a potential target for developing novel treatments to alleviate cognitive deficits in afflicted patients. Neural plasticity is also important for proper neurotransmission between the motor neuron and muscle fiber, and the team has further identified a signaling protein downstream of EphA4 which is essential for maintaining muscle strength and proper motor function, thus shedding new light on the treatment of neuromuscular disorders such as muscular dystrophy. These groundbreaking discoveries were published in Nature Neuroscience and Neuron, two of the most prestigious journals in neuroscience.

Development of Therapeutic Drugs for Clinical Application
The project has yielded a portfolio of novel and promising compounds with potential clinical applications in Alzheimer’s disease and insomnia, as indicated below. Patent applications have been filed for these. The team has also identified TCM herbs as active drug leads against targets associated with Parkinson’s disease and depression.

Neuroprotective compounds and drug leads for Alzheimer’s disease
Subtype-specific melatoninergic agonists
for sleep-related ailments
Herb fractions and drug leads for
depression and Parkinson’s disease
The compounds are in various stages of pre
-clinical development, and due to the unique drug discovery strategy undertaken by the AoE team, one or more of these have been explored by pharmaceutical companies for potential collaboration and further development towards clinical trials.


Prof Nancy Ip also delivered a RGC public lecture titled “From Neuroscience Discoveries to Promoting Human Health” and shared the research achievements of the “Molecular Neuroscience: Basic Research & Drug Discovery” project at Hong Kong Science Museum.

Strategic Partnerships with Leading Global Pharmaceutical Companies
The AoE team has strived hard to build ties with the biopharmaceutical industry in the form of collaborations and/or development partners to strengthen and enhance both the basic research and drug development aspects of the AoE. For example, GlaxoSmithKline (GSK) R&D China, a China-based subsidiary of GSK, a leading pharmaceutical company, have expressed their interest in the AoE deliverables and are keen to develop long-term drug discovery projects for co-development of selected lead compounds. A strategic alliance between HKUST and GSK R&D China was established in 2009. The collaborative work between the two organizations is aimed at identifying drug leads for the treatment of neurodegenerative disorders. A joint “GSK R&D China - HKUST Neuroscience Laboratory” has been established at HKUST for this purpose. The industry-academia partnership between GSK and HKUST is unique in that it brings the biomedical expertise in industry together with the biological expertise within academia to address an emerging area of neuroscience. This is an important strategic alliance as it not only brings attention to the high level of research being undertaken at HKUST but also places Hong Kong prominently on the global R&D map.

Other Major Accomplishments
State Key Laboratory
In recognition of the achievements made under the AoE Scheme, in 2010, the Ministry of Science and Technology approved the establishment of the “State Key Laboratory (SKL) of Molecular Neuroscience” at HKUST, the first and only SKL at HKUST. The SKL Scheme identifies accomplished scientists undertaking pioneering research to support China’s technological development. Hence, this national standing represents the Chinese Government’s recognition of HKUST’s unremitting efforts and excellence in conducting neuroscience research and development. Armed with this distinction, the Laboratory aims to become one of the world’s leading research centers in this discipline - to advance basic research in molecular neuroscience, and to stimulate the formation of new biotechnology ventures in China.

Publications and Lectures
Over the course of the AoE project, the breakthrough research undertaken by the team resulted in a vast output of publications in prestigious international journals such as Cell, Science, Nature Cell Biology, Molecular Cell, Nature Neuroscience, Neuron, Nature Structural Biology, PLoS Biology, Journal of Cell Biology, PNAS, Journal of Neuroscience, and Journal of Biological Chemistry. To date, the AoE team has published over 600 research papers in areas including neural development and functions, neuronal signaling mechanism, and structure-function relationship of neuroproteins. Team members have also been invited to deliver plenary or symposium lectures at over 300 international conferences and workshops, as well as invited to write review articles on specific subjects in these research areas. The AoE team has actively promoted their breakthrough findings through international symposiums and conferences such as the prestigious Gordon Research Conference, a bi-annual event attended by leading neuroscientists and Nobel laureates, and by organizing the Molecular Neuroscience Seminar Series and the Croucher Advanced Study Institute.

Education and Training Opportunities for Young Local Scientists
The AoE project has contributed to student training and skills development in the area of molecular neuroscience. Since its inception, more than 120 postgraduate students (PhD, MPhil and MSc) in participating departments have been actively involved in the AoE project. The students have acquired invaluable handson training in advanced technologies while sharpening their research proficiency. The AoE project has also contributed significantly to the training of over 40 undergraduate students annually.

Looking Forward
A rapidly aging population and the resulting increased prevalence of brain diseases has led to a global undertaking to seek effective measures to prevent, diagnose and treat brain diseases. The development of molecular neuroscience in Hong Kong, and the unique research model of combining molecular science with TCM-based drug development, promises to boost biomedical research and drug discovery to identify new clinical applications. The significance of this AoE project and the resulting outputs contribute towards this global undertaking. Through our basic research and drug discovery activities, the program is uniquely positioned to enable the translation of neuroscience research discoveries into therapies for the benefit of patients. The project has essentially placed Hong Kong on the map of advanced molecular neuroscience research while contributing to the development of a local biopharmaceutical industry.

Project Coordinator:
Prof Nancy IP
The Hong Kong University of
Science and Technology