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Nucleic Acid Therapeutics for Childhood Genetic Disorders - PI: Haiyan Zhou
The Zhou Lab focuses on developing RNA oligonucleotide therapies for rare childhood disorders, by using the state-of-the-art nucleic acid technology, and to translate these experimental therapies to clinical applications. Our nucleic acid therapy (NAT) programme covers topics on the identification of novel therapeutic targets, design of different RNA therapeutic approaches (ASO, siRNA, microRNA, RNA/gene editing and mRNA), tissue/cell-specific delivery, validation in different model systems (cellular and animal), downstream functional assays and the eventual clinical translation. We have applied this technology to a wide range of genetic disorders and worked closely with UCL colleagues on conditions such as muscular dystrophies (Francesco Muntoni and Jennifer Morgan), respiratory disorders (Hannah Mitchison and Stephen Hart), neurological conditions (Mary Reilly, Manju Kurian, and Amy McTague), inborn errors of metabolism (Paul Gissen, Philippa Mills, Wendy Heywood and Karin Tuschl) and vasculitis (Ying Hong and Despina Eleftheriou).
In addition to the NAT research programme, the Zhou lab has longstanding history in translational research in neuromuscular disorders, including spinal muscular dystrophy, congenital myopathy and muscular dystrophies. Our research interests range from the identification of novel disease mechanisms, therapeutic targets and biomarkers to the development of novel molecular and cellular therapies. For neuromuscular disorders, the Zhou lab works closely with Professor Francesco Muntoni and the Dubowitz Neuromuscular Centre at Great Ormond Street Institute of Child Health.
The Zhou lab is a key training hub for numerous training programmes, including e-COST Action CA17103 on Delivery of Antisense RNA Therapeutics (DARTER), Marie Skłodowska-Curie Innovative Training Networks PhD fellowship (H2020-MSCA-ITN-2020), China Scholarship Council Training Programme, UCL Child Health Research PhD Programme, and UCL MSc and iBSc research projects.
Main Funding: The Wellcome Trust, UK Research and Innovation, NIHR GOSH BRC, The Royal society, Harrington Discovery Institute, Muscular Dystrophy UK, SMA Europe, UCL Technology Fund, Roche Pharmaceuticals.
Team Members
Project Manager:
- Catherine Ryan
Senior Research Fellow:
Research Fellows:
- Dr Charalambos Demetriou*
- Dr Anna Kowala
- Dr Tomasz Tomkiewicz*
- Dr Reddy Vootukuri*
- Dr Qiang Zhang
Research Assistants:
- Sean Briggs
- Hou Wang Lam*
- Shunyi Ma
- Elena Tybulewicz
Clinical Fellow:
PhD Students:
- Barbora Cerna*
- Shuzhi Cheng
- Fady Guirguis*
- Parth Patel
- Kazimir Uzwyshyn-Jones
Visiting staff / Student:
- Cathy Lin
- Jannatun Nahar
*Joint supervision
Key references
(A full list of publications can be found at https://iris.ucl.ac.uk/iris/browse/profile?upi=HZHOU13)
- Lange, J., Zhou, H., & McTague, A. Cerebral Organoids and Antisense Oligonucleotide Therapeutics: Challenges and Opportunities. Front Mol Neurosci. 2022 Jun 27;15:941528
- Zhou, H. Design of Bifunctional Antisense Oligonucleotides for Exon Inclusion. Methods Mol Biol. 2022;2434:53-62.
- Zaharieva, I. T., Scoto, M., Aragon‐Gawinska, K., Ridout, D., Doreste, B., Servais, L., Muntoni, F., Zhou, H. Response of plasma microRNAs to nusinersen treatment in patients with SMA. Annals of Clinical and Translational Neurology. 2022 Jul;9(7):1011-1026.
- Spicer, C., Lu, C. H., Catapano, F., Scoto, M., Zaharieva, I., Malaspina, A., Greensmith, L., Muntoni, F., Zhou, H. The altered expression of neurofilament in mouse models and patients with spinal muscular atrophy. Annals of Clinical and Translational Neurology. 2021 Apr;8(4):866-876.
- Aguti, S., Bolduc, V., Ala, P., Turmaine, M., Bönnemann, C. G., Muntoni, F., & Zhou, H. Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD. Molecular Therapy : Nucleic Acids, 2020; 21, 205-216.
- Aguti, S., Marrosu, E., Muntoni, F., & Zhou, H. Gapmer Antisense Oligonucleotides to Selectively Suppress the Mutant Allele in COL6A Genes in Dominant Ullrich Congenital Muscular Dystrophy. Methods Mol Biol. 2020;2176:221-2306
- Zhou, H., Meng, J., Malerba, A., Catapano, F., Sintusek, P., Jarmin, S., Feng, L., Lu-Nguyen, N., Sun, L., Mariot, V., Dumonceaux, J., Morgan, JE., Gissen, P., Dickson, G., Muntoni, F. Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy. J Cachexia Sarcopenia Muscle. 2020 Jun;11(3):768-782.
- Zhou, H., & Muntoni, F. (2020). The authors reply: Letter on: "Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy" by Zhou et al . Journal of Cachexia, Sarcopenia and Muscle, jcsm.12608. doi:10.1002/jcsm.12608
- Bolduc V, Foley AR, Solomon-Degefa H, Sarathy A, Donkervoort S, Hu Y, Chen GS, Sizov K, Nalls M, Zhou H, Aguti S, Cummings BB, Lek M, Tukiainen T, Marshall JL, Regev O, Marek-Yagel D, Sarkozy A, Butterfield RJ, Jou C, Jimenez-Mallebrera C, Li Y, Gartioux C, Mamchaoui K, Allamand V, Gualandi F, Ferlini A, Hanssen E; COL6A1 Intron 11 Study Group, Wilton SD, Lamandé SR, MacArthur DG, Wagener R, Muntoni F, Bönnemann CG. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. JCI Insight. 2019 Mar 21;4(6):e124403.
- Zhou, H., & Muntoni, F. Morpholino-Mediated Exon Inclusion for SMA. Methods Mol Biol. 2018;1828:467-477
- Aguti, S., Malerba, A., & Zhou, H. The progress of AAV-mediated gene therapy in neuromuscular disorders. Expert Opinion on Biological Therapy, 2018;18 (6), 681-693.
- Sardone, V., Zhou, H., Muntoni, F., Ferlini, A., & Falzarano, M. S. Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease. Molecules. 2017 Apr 5;22(4):563.
