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.
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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
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