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Targeting sclerostin loop3 to promote bone formation with low cardiovascular risk in animal models
The role of the interactions between N domain and Linker 2 of DKK1 in modulating the immunosuppressive tumor microenvironment mediated by DKK1C domain

20162023

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Personal profile

Chinese Name

于媛媛

Research Interests

1) Optimization of aptamer selection methodology;

2) Aptamer-based translational medicine and drug discovery;

3) aptamer structural biology

Biography

Dr. Yuanyuan Yu is currently an Assistant Professor in the School of Chinese Medicine. She obtained her PhD in the Department of Biochemistry from Faculty of Medicine, the University of Hong Kong in 2015. After graduation, she joined School of Chinese Medicine, Hong Kong Baptist University to undertake the postdoctoral training from 2015 to 2019. Dr. Yu was promoted to Research Assistant Professor in 2019 and Assistant Professor in 2022, and undertaking multiple external grants in the capacity of PI (such as GRF from RGC). Since her PhD study, Dr. Yu has been working on the development of therapeutic aptamers against various diseases.  Dr. Yu’s research are mainly focus on aptamer-based drug discovery, including the disease mechanism, target understandings and drug discovery of diseases (especially rare diseases that lack specific drugs and geriatric diseases).

1. Clinical challenges

Osteoporosis is an important public health problem in the world, and osteogenesis imperfecta is a rare genetic bone disease in children. Promoting bone formation is an effective strategy for the treatment of both diseases. However, the marketed sclerostin antibody has serious cardiovascular risks. For a new osteogenic drug against chronic diseases, it is necessary to avoid this cardiovascular risk. Therefore, it is required to develop a new generation of sclerostin inhibitors with cardiovascular safety.

2. Main Research

  2.1 Molecular targets: To develop a new generation of cardiovascular-safe sclerostin inhibitors, it is necessary to find out whether there are specific structural domain on sclerostin that are not involved in cardiovascular protection but participate in the inhibition of bone formation. Dr. Yu’s research found that sclerostin loop 3 depletion promotes osteogenic potential but does not affect cardiovascular system. This discovery provides a molecular target direction that is crucial for drug discovery to solve the cardiovascular safety problem of bone anabolic therapy.

  2.2 Drug discovery: Dr. Yu’s team then screened, designed, and synthesized the aptamer Apc001 specifically targeting sclerostin loop 3 based on the research results of the above molecular targets, and evaluated the effect of Apc001 in animal models of osteoporosis and osteogenesis imperfecta. It was found that Apc001 can effectively promote bone formation without increasing the risk of cardiovascular disease.

3. innovation impact

  3.1 Patents: Apc001 related patents include China CN111712573A; International WO2019/154410; US 1547/34 PCT/US; Japan 20-5553-XY; European EP3754021A1.

  3.2 FDA Approval: Apc001 for the treatment of Osteogenesis Imperfecta has obtained FDA Orphan Drug Designation and Pediatric Rare Disease Drug Designation, which is the first aptamer drug in China to receive Orphan Drug and Pediatric Rare Disease Drug Designation. The research team is preparing to enter the pilot test stage in order to actively promote the process of IND in both China and the United States for Apc001.

  3.3 Science and technology exhibition: Apc001 was elected as one of the 30 representative achievements in the field of medical and health sciences in the 25th anniversary of the return of the Hong Kong Special Administrative Region, and participated in the innovation and technology exhibition.

  3.4 Research platform: In order to integrate academic and research resources and promote the development of aptamer drugs in treatment and diagnosis, the candidate assisted in the establishment of the "Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP)" in Hong Kong Science Park (https://www.hkaptamer.com) and served as the platform manager.

4. Impact

 4.1 New drug development strategies for the treatment of osteoporosis and osteogenesis: There is no drug company developing a sclerostin inhibitor without cardiovascular risk. Based on Dr Yu's research on Apc001, at least two drug pharmacies have participated in the development of sclerostin inhibitors without cardiovascular risk. Among them, Aptacure Therapeutics Ltd. cooperated with Dr. Yu’s team for the clinical translation of Apc001, which received funding support from the "Biomedical Technology Incubio Program" of Hong Kong Science Park, and is discussing with Shanghai Pharmaceuticals, one of the world's top 500 companies, for co-development of Apc001. Based on Dr. Yu’s finding on sclerostin loop3, Guangzhou Nerin Medical Technology has carried out the research and development of small molecule inhibitors targeting loop3.

 4.2 Aptamer Drug Valley: Under the coordination of the HKAP platform, a number of pharmaceutical companies have settled in the Hong Kong Science Park to carry out aptamer-related drug research and development, including Aptacure, Increase, Shanghai Pharma, forming a characteristic aptamer drug valley.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

PhD, The University of Hong Kong

1 Sept 201021 Nov 2015

Award Date: 21 Nov 2015

External positions

Guangdong‐Hong Kong Macao Greater Bay Area International Research Platform for Aptamer‐Based Translational Medicine and Drug Discovery

1 Jan 2017 → …

Keywords

  • QH301 Biology
  • Biochemistry
  • Molecular Biology
  • RM Therapeutics. Pharmacology
  • Drug Discovery
  • Aptamer

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