RGC Newsletter - Research Frontiers

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.