Tag: Hong Kong

A research team led by Hong Kong Baptist University (HKBU) has identified a molecular target for bone anabolic therapies using a selected aptamer that serves as an inhibitor of sclerostin, a protein that prevents bone growth. The discovery offers hope for the development of an effective next-generation treatment for osteoporosis and osteogenesis imperfecta that is free of cardiovascular risk compared to the marketed antibody drug.

The research findings have been published in the international academic journals Nature Communications and Theranostics. The new drug is at the pre-clinical trial development stage, and the research team plans to start clinical trials in the US and on the Mainland in 2024.

Current medication increases cardiovascular risk

Osteoporosis is a metabolic condition which leads to a reduction in bone density, resulting in weakened bones that are more fragile and likely to break. Osteogenesis imperfecta, also known as “brittle bone disease”, is a rare congenital genetic disorder characterised by extremely fragile bones. Sclerostin has been identified as a therapeutic target for both diseases.

In 2019, the US Food and Drug Administration (FDA) approved the use of the monoclonal antibody against sclerostin for the treatment of postmenopausal osteoporosis. Studies have also shown that sclerostin antibody enhances bone mass and bone strength of mice with osteogenesis imperfecta. However, as sclerostin plays a protective role in the cardiovascular system, it was seen that sclerostin antibody increased the risk of heart attacks, stroke and cardiovascular death during clinical trials. Therefore, a black box warning for potential cardiovascular risks is required by FDA.

A research team led by Professor Lyu Aiping, Dr. Kennedy Y.H. Wong Endowed Professor in Chinese Medicine and Director of the Institute of Integrated Bioinformedicine and Translational Science at HKBU; Professor Zhang Ge, Director of the Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases at HKBU; and Dr Yu Yuanyuan, Manager of the Guangdong-Hong Kong-Macau Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery and Assistant Professor of the School of Chinese Medicine at HKBU, endeavoured to develop alternative drug options.

“loop3” identified as a new therapeutic target

Sclerostin suppresses bone formation by antagonising the “Wnt signalling pathway”. The “Wnt signalling pathway” modulates the stem cells responsible for skeletal tissue regeneration. Therefore, inhibition of sclerostin promotes bone growth.

The research team discovered that a “loop3 domain” in the core region of sclerostin can be used as a molecular target to inhibit sclerostin. Through genetic studies, it was shown that deficiency of the loop3 domain can inhibit sclerostin’s antagonistic effect against the Wnt signalling pathway, but it does not affect the cardiovascular protective effect of sclerostin. The result suggests that the loop3 domain can serve as a molecular target for inhibiting sclerostin while preserving its cardiovascular protective function.

The researchers then proceeded to screen aptamers that can specifically inhibit sclerostin loop3. Aptamers are single-stranded DNA or RNA molecules that can selectively bind to molecular targets such as proteins. After binding with specific proteins, aptamers may inhibit protein–protein interactions and thereby elicit certain therapeutic effects. Through a combinatorial technology, an aptamer “aptscl56” was selected as a potential sclerostin inhibitor that targets the loop3 structure.

Aptamer selected as effective and safe sclerostin inhibitor

The research team examined aptscl56’s therapeutic functions with osteoporotic rat models and osteogenesis imperfecta mouse models. They found that aptscl56 effectively promots bone formation. On the other hand, the application of aptscl56 does not increase the risk of developing cardiovascular diseases such as aortic aneurysms and atherosclerotic development in both models.

The medical use of aptamers confers certain advantages, such as thermal stability and ease of synthesis. However, they are prone to rapid degradation and renal filtration. The research team therefore modified aptscl56 to produce an aptamer named “Apc001” with a longer half-life. The team demonstrated that Apc001 promotes bone formation, increases bone mass, improves bone microarchitecture integrity, and enhances bone mechanical properties in rats with osteoporosis and mice with osteogenesis imperfecta.

Clinical trials due to start in 2024

“Searching for reliable and safe alternatives to overcome the limitations of the currently available drugs is crucial to help patients who need bone anabolic therapies. Our ongoing studies, which span from identifying molecular targets for sclerostin inhibition to aptamer drug discovery, offer hope for the development of next-generation sclerostin inhibitors in the near future,” said Professor Zhang Ge.

“Our search for alternative drugs for bone anabolic therapies is a good example of tripartite collaboration between academia, industry and the government. The research work was partly conducted in collaboration with a local biotechnology company, and it was supported by the Innovation and Technology Fund. Some biotechnology companies in the Mainland were engaged in certain aspects of developmental research for the aptamer, such as toxicology tests. The collaborative efforts will continue to create more synergy and fruitful results,” said Professor Lyu Aiping.

The therapeutic aptamer Apc001 was granted orphan drug designation by the FDA for the treatment of osteogenesis imperfecta in 2019.

Research led by Hong Kong Baptist University (HKBU) involving the use of a pioneering female sterility technique has led to a breakthrough in the production of hybrid rice seeds. Compared to the commonly used “three-line” male sterility technique in hybrid rice seeds production, the novel approach enhances the efficiency of hybrid rice production by eliminating rice seeds that have been produced due to the self-pollination of the “restorer line”. The novel technique enables fully automatic harvesting of hybrid seeds by machines, which can substantially reduce harvesting costs. The research results have recently been published in Cell Research, a top-ranking international scientific journal.

Male sterility technique incurs high harvesting costs

Self-pollinating plants are known to maintain their genome homozygosity, and as a result, their offspring can have the same features over generations.

Heterosis, which refers to the increased rate of growth due to genome heterozygosity as a result of the hybridisation of distant parents, is difficult to exploit with self-pollinating plants. In nature, rice is usually bred using self-pollination. However, over the past few decades, scientists – following pioneering work by Professor Yuan Longping, the “Father of Hybrid Rice” – have developed hybrid rice breeding techniques by exploiting sterile male genes, and these techniques can produce hybrid seeds with the normally self-pollinating rice plants in large quantities. China and other countries around the world have extensively used the male sterility technique to produce hybrid rice seeds, and it has led to a substantial increase in rice yields.

The male sterility technique first breeds cultivars, i.e. plant varieties, of the “male-sterile line” of rice as pollen receivers. Rice cultivars from the “restorer line” with normal fertility act as pollen donors, and they are grown close to the “male-sterile line” to facilitate pollen transfer for hybridisation. However, self-pollinating seeds can also be produced by the “restorer line”, and they must be removed manually to avoid mixing them up with the hybrid seeds before mechanical harvest, resulting in high harvesting costs. In theory, using sterile female rice as the “restorer line” is ideal because it cannot produce any self-pollinated seeds. However, this approach has not been adopted because the germplasm of sterile female rice remains extremely rare in nature and sterile female plants find it difficult to self-reproduce.

TFS1 mutation exhibits female sterility

After nearly a decade of ongoing study, a research team led by Professor Zhang Jianhua, Chair Professor of the Department of Biology at HKBU, has managed to identify a “spontaneous thermo-sensitive female sterility 1” (TFS1) gene mutation in an elite rice cultivar during paddy field production. This genetic mutation exhibits female sterility under regular or high temperature conditions (i.e. above 25°C), and fertility is partly resumed under low temperature conditions (i.e. 23°C). It does not have any defects in terms of its vegetative growth.

The team observed that rice with the TFS1 gene mutation can produce healthy pollen with normal male fertility. Rice with normal fertility can produce normal seeds after receiving pollen from rice with the TFS1 gene mutation. Further investigations revealed that under regular or high temperature conditions, after pollen has landed on the stigma of rice with the TFS1 gene mutation, pollen tubes that have grown from the pollen cannot enter the embryo sac. The embryos therefore fail to develop and seeds cannot be produced. But under low temperature conditions, the ability to fertilise and develop embryos is partially recovered.

Following genetic analysis using gene cloning and molecular techniques, the team found that the female sterility mutation is created by a point mutation in the genic region of Argonaute7 (AGO7), a member of the Argonaute (AGO) protein complex that is responsible for the production of many small interfering RNAs, namely tasiR-ARFs. The downstream regulation of these tasiR-ARFs regulates the pollen tube entrance into the embryo sac, but it failed under regular or high temperature conditions in the rice with TFS1 mutation, and hence double fertilisations cannot be achieved.

No need to remove “restorer lines” before harvest

To evaluate the potential of using TFS1 as a genetic tool for hybrid rice production, the team conducted field trials in Hong Kong and Hunan Province in mainland China. The TFS1 gene mutation was introduced into three cultivars of rice by introgression and genome editing to create the germplasms with thermo-sensitive female sterility. They acted as the “restorer lines” for pollen donation. Another three cultivars of rice with male sterility were used as the “male-sterile lines”.

The team planted the “restorer lines” separately next to the “male-sterile lines” as in traditional hybrid breeding, or randomly mixed them on the farm when planting. In both planting arrangements, more than 30% of the panicles of the “male-sterile lines” in Hong Kong, and 40% in Hunan Province produced hybrid seeds. The proportion of seed sets is similar to the hybrid production yields using existing “restorer lines”, but the hybrid rice seeds can be harvested without the removal of the “restorer lines”.

Great commercial potential with reduced harvesting costs

Professor Zhang said: “Nowadays, producing hybrid rice seeds is still a labour-intensive process in agriculture. Female sterility, if it can be introduced into a ‘restorer line’ as a pure pollen donor, has great potential to reduce the cost, because the male and female parents of hybrid rice can be grown and harvested together by machines without worrying about seed purity.

“Our research findings provide a suitable trait for fully mechanised hybrid rice breeding, and our genetic tool has shown great promise for commercial applications. To maximise rice yields, we need further large-scale field trials to improve the receptibility between female and male-sterile lines.”

Apart from researchers from HKBU, the research team included scientists from the Hunan Agricultural University, the Guangdong Academy of Agricultural Sciences, the University of California at Davis, and the National Agriculture and Food Research Organisation in Japan.

Organised by the Academy of Film (AF) at Hong Kong Baptist University (HKBU), the Global University Film Awards (GUFA) 2022 held its magnificent award presentation ceremony in virtual mode on 11 November. The entry from France’s Le Fresnoy clinched the Gold Award. (The full list of winners is attached in the appendix at the end of this article).

This year’s award presentation ceremony was broadcast live online in a wonderfully designed cinematic setting, using virtual sets and advanced technology to recreate classic scenes in blockbusters such as The Matrix, the Harry Potter film series, and In the Mood for Love. In his opening remarks at the ceremony, Dr Clement Chen, Chairman of the Council and the Court of HKBU, shared the delights of seeing GUFA held for the third time. “We hope to stand as a beacon of encouragement to emerging filmmakers, allowing them to create their art without commercial considerations and industry pressures. At university, they are free to let their imagination fly, share their concerns and explore creative ideas. We at HKBU embrace these ideals and, for over four decades, have been offering the finest teaching and training in the cinematic arts. We continue to celebrate this legacy today as we nurture tomorrow’s filmmakers.”

In his speech, Professor Alexander Wai, President and Vice-Chancellor of HKBU, said: “HKBU is the first institution in Hong Kong to offer film and video production programmes and we always have our eyes on the future. Filmmaking is a global community, and GUFA is a way for all of us to celebrate new young talents from all over the world. It gives me great delight to have a sneak peek at the future voices of filmmaking and to celebrate their progress.”

Widely known as the “University Oscars”, this year GUFA received more than 2,300 submissions from about 100 countries and regions. Celebrated professionals in the film industry, including directors Ms Mabel Cheung, Mr Derek Tsang, Ms Jessey Tsang, Mr Ray Yeung, and actress/producer Ms Josie Ho presented 15 awards to young film talents from all over the world, letting them shine on a glamorous virtual stage.

To further showcase the exemplary works at GUFA 2022, a public screening of the winners was held on 15 November at HKBU. Members of the public were welcome to attend. For more information, please refer to the GUFA website, GUFA Facebook page and GUFA YouTube channel.

GUFA recognises the excellence of film productions by university students from across the world by connecting the global film community and its audiences with outstanding work and groundbreaking ideas presented by the participants. The event not only showcases the students’ talents but also fosters the exchange of ideas and enhances professional networks, building synergy between young regional talents and the international creative industry.

Appendix: Award winners

A Hong Kong Baptist University (HKBU) collaborative research team has synthesised a nanoparticle named TRZD that can perform the dual function of diagnosing and treating glioma in the brain. It emits persistent luminescence for the diagnostic imaging of glioma tissues in vivo and inhibits the growth of tumour cells by aiding the targeted delivery of chemotherapy drugs. The nanoparticle offers hope for the early diagnosis and treatment of glioma, especially cerebellar glioma, which is even harder to detect and cure with existing methods.

The research results have been published in Science Advances, an international scientific journal.

Limitations of existing diagnostic and therapeutic approaches

Glioma is the most common form of malignant primary brain tumour, and it accounts for about one-third of all brain tumours. Magnetic resonance imaging (MRI) is commonly used to diagnose glioma, but the technology is not that sensitive. Cerebellar glioma, a relatively rare brain tumour, is even harder to detect with MRI. To facilitate early detection and treatment, an alternative method with improved sensitivity and precision is needed to diagnose glioma.

Doxorubicin, a chemotherapy agent, is an effective treatment for glioma. However, its application may also damage normal cells, and it is associated with a range of side effects. To enhance doxorubicin’s clinical efficacy and minimise its side effects, a novel approach is needed to apply the drug to tumour cells in a more targeted manner.

In response to the diagnostic and therapeutic needs of glioma, a research team co-led by Dr Wang Yi, Assistant Professor of the Department of Chemistry at HKBU, and Professor Law Ga-lai, Professor of the Department of Applied Biology and Chemical Technology at the Hong Kong Polytechnic University, has synthesised a novel near-infrared (NIR) persistent luminescence nanoparticle called TRZD, which can play a dual role in diagnostic imaging and as a drug carrier for glioma.

TRZD has the characteristic of emitting NIR persistent luminescence after excitation with ultraviolet (UV) light. The basic structure of TRZD is a combination of nanoparticles, loaded with the mesoporous structure of silica, which makes it a good carrier of doxorubicin particles. Its surface is coated with red blood cell membranes to increase its stability, and it is embedded with T7 peptides. T7 peptides have a strong affinity for transferrin receptors which are abundant on the surface of tumour cells, and they can facilitate TRZD’s penetration through the blood-brain barrier.

An imaging probe for glioma diagnosis

The research team evaluated the efficacy of TRZ (i.e. TRZD without doxorubicin) in diagnostic imaging for glioma with a mouse model. TRZ particles were first excited by UV light to initiate luminescence. Mice with tumour tissues injected into their cerebrum and cerebellum were then treated with TRZ. In the following 24 hours, TRZ luminescence was detected at the tumour sites of the mice.

However, when the same experiment was conducted with TRZ without T7 peptides, and TRZ without both the red blood cell membrane coating and T7 peptides, no luminescence was detected at the tumour sites of the mice. The results show that the red blood cell membrane coating can prolong the function of TRZ by stabilising the nanoparticle, and it can slow down its natural uptake by the human body. On the other hand, T7 peptides are instrumental in TRZ’s penetration into and accumulation in tumour cells, so that it can perform its imaging function for glioma.

Dr Wang said: “Our experiment suggests that TRZ is a promising bioimaging agent for the diagnosis of glioma. It was observed that TRZ’s luminescence can be detected in tumour cells in both the cerebrum and cerebellum regions of the brain, which is an encouraging result because glioma in the cerebellum region is difficult to detect with existing diagnostic methods. As a result, TRZ offers new hope for the timely and accurate diagnosis of glioma.” 

TRZD inhibits the growth of glioma and extends the lifespan of mice

The research team further evaluated the anti-tumour efficacy of TRZD using a group of mice who had had their cerebrum and cerebellum injected with tumour tissues. After applying TRZD for 15 days, the average diameter of their tumours was reduced to 1 mm. They also survived 20 days longer on average compared to the control group, who had not received TRZD. Besides, cell death was observed in the tumour region but not in normal brain tissue.

Dr Wang said: “The experimental results indicate that TRZD’s therapeutic effect on glioma has good selectivity, because doxorubicin is brought specifically to tumour cells due to T7 peptide’s strong affinity with tumour cells’ surface receptors and its ability to penetrate the blood-brain barrier. As a result, doxorubicin can be applied in a more targeted manner, and hopefully its side effects can be minimised with a reduced drug dosage.

“We concluded that TRZD demonstrates promising potential, and it could be developed into a new generation of anti-glioma drugs that can perform the dual function of diagnosis and treatment. It also offers hope for the development of treatment protocols for other brain diseases.”