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This Centre is able to spearhead activities in this rapidly evolving area and play a major role in translational neuroscience in UCL.
The Genetic Therapy Accelerator Centre (GTAC) is led by听Professor Francesco Muntoni, an Internationally recognised Paediatric Neurologist with dual appointments at UCL QS Institute of Neurology and听Director of the Dubowitz Neuromuscular Centre听at the UCL听Institute of Child Health and Great Ormond Street Hospital for Children. The Genetic Therapy Accelerator Centre, a new gene therapy translational research partnership, is a cross-faculty collaboration within UCL to drive forward an exciting evolving area with direct therapeutic benefits for patients with disabling neurological conditions.
The foundation of the centre builds on his pioneering work in the first genetic therapies for neuromuscular disorders and the vision to apply this knowledge and experience to develop the next generation of genetic therapies for a range of neurological disorders. The revolution in genomics has led to an explosion of potential genetic targets as novel therapeutic targets.听
In the last five years a number of extremely effective RNA and adeno-associated viral vectors (AAV) therapies have dramatically improved the outcomes for individuals affected by a range of neurological disorders, mostly affecting children. The focus of the centre听is to harness the learning derived from these recent successes, mechanistic insight discovery, to early and late translational research and eventually regulatory approval, and apply it to a wider group of neurodegenerative disorders.听听
The centre combines laboratory and clinical expertise focused on neurological, neuromuscular and neurodegenerative disorders, their mechanisms of disease and cutting-edge RNA and AAV gene therapy expertise, and foster cross-institutional collaborations between IoN QS and GOS ICH. Professor Muntoni, along with his team lead the research programmes in translational AAV and RNA therapeutics and听provide expert听advice and support to other departments at IoN QS and GOS ICH on translational genetic therapy developments from proof of concept, preclinical studies of efficacy and safety towards clinical translation.
The Centre develops links and synergies with other related activities including the听Sigrid Rausing Trust Initiative, Dementia Research Institute, LMIC International Centre for Neuromuscular Diseases, Neurogenetics Therapies Programme,听the two Biomedical Research Centres at IoNQS听and GOSICH, and the听genetic therapy Initiatives at the Zayed Centre for Research into Rare Disease in children.
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- Aadeno Associated Viral Vectors听Therapies
Adeno-associated viral vectors are a leading modality to deliver genetic therapies showing profound disease modifying impact on neurological disorders resulting in FDA approval for AAV gene therapies for spinal muscular atrophy, neurotransmitter disorder AADC deficiency and Duchenne muscular dystrophy. 听Dr Jo Ng leads preclinical translational AAV gene therapy development for neurological disorders such as dopamine transporter deficiency syndrome, infantile and juvenile parkinsonism and epileptic encephalopathy. Dr Ng collaborates with experts in clinical disease, genetic disease mechanism to develop clinically translatable AAV gene therapies. In addition Dr Ng works closely with AAV researchers to develop the technology to improve AAV transduction efficiency, selectivity and safety.听Dr Ng is available on a monthly basis to discuss AAV projects with interested researchers to support queries from capsid selection, construct design, vector production to听in vivo听experimental design.听
Project:听AAV gene therapy for Tyrosine hydroxylase deficiency syndrome AAV gene therapy for DNAJC6 juvenile parkinsonism AAV gene therapy for Dopamine transporter deficiency syndrome.听Peripheral Nerves made fluorescent with AAV vector.
- Related Publications:
- 听Ng J, Barral S, Waddington SN, Kurian MA.听Mov Disord. 2023 Jun;38(6):924-936. doi: 10.1002/mds.29416. Epub 2023 May 5.听PMID:听37147851听Review.
- 听Ng J, Barral S, Waddington SN, Kurian MA.听Cells. 2023 Jun 28;12(13):1737. doi: 10.3390/cells12131737.听PMID:听37443770听Free PMC article.听
- Reviews
- Novel AAV capsids (Dr John Counsell, Dr Killian Hanlon)
- Cell therapy for Dopamine Transporter deficiency syndrome (Dr Serena Barral, Prof Manju Kurian)听
- Novel CNS promoters for AAV neurological gene therapy (Dr Riccardo Privolizzi, Professor Kevin Truong)
Collaborations:听AAV gene therapy for devastating epileptic encephalopathy (Dr Raj Karda, Professors Stephanie Schorge, Simon Waddington, Cathy Abbott, Rocket Pharma ) AAV gene therapy for sodium channelopathy (Dr Juan Antinao-Diaz)
- Ribonucleic Acid听Therapies
Dr Sara Aguti is a molecular biologist with a profound interest in the development of RNA therapies to address unmet clinical needs. Sara holds a European PhD in Neuroscience from the University of Florence (Italy) and University College London. With over four years of postdoctoral experience at UCL Great Ormond Street Institute of Child Health, under the guidance of Professor Muntoni and Dr Haiyan Zhou, and one year at MINA therapeutics, Sara has acquired extensive expertise in RNA therapies, particularly in antisense oligonucleotide (ASO) therapy. During her post-doc she developed an ASO therapy for collagen VI related congenital muscular dystrophy, a rare disorder for which a cure is currently unavailable. Her work has generated several awards, including travel grants to present her research at national and international conferences, the WMS poster prize and the Dubowitz Prize in 2020. Additionally, she has filed three patents and received support from organizations like BRC, TIN, MDUK, and LifeArc for her translational research. Currently, Sara鈥檚 primary focus revolves around the development of ASO-peptide targeted delivery methods in various cells and tissues to overcome the challenges associated with ASO in vivo delivery. Sara joined the GTAC team to support RNA therapy development for neurological and neuromuscular disorders at IoN.听Her specific contributions include providing assistance in designing and chemically optimizing ASO sequences, optimizing ASO in vitro screening procedures, and refining in vivo delivery methods.
- In Vitro Oligo Screening: Assistance in designing of in vitro screening assays for oligos.
- In Vivo Oligo Delivery: Assisting in optimizing delivery methods to ensure efficient and effective delivery to the desired tissues or cells.
Grants awarded 2023-2024:
- Off-target, toxicity and biodistribution analysis of cell-targeted RNA therapy for collagen VI-related congenital muscular dystrophies. Rosetrees Trust Seedcorn Award 拢10k May 2024-2025. (PI Aguti, Zhou and Muntoni co-investigator)
- Developing peptide-conjugated antisense oligonucleotide therapy for COL6-related congenital muscular dystrophy. Million Dollar Bike Ride $70,000, May 2024-2025. (PI Zhou, Aguti and Muntoni co-investigator).
- TargetRide: Peptide-Guided RNA Therapeutic Transport System. UCL Technology Fund 拢250,000, June 2024-2025. (PI Zhou, Aguti and Muntoni co-investigator).
- Preclinical development of peptide-conjugated antisense oligonucleotide therapy for COL6-related congenital muscular dystrophy. LifeArc- Muscular dystrophy UK translational research fund 拢329,000. 2024-2026. (PI Zhou, Aguti, Muntoni, Bonnemann, Lench, Bolduc, Oliver co-investigator.)
- Preclinical development of a targeted antisense oligonucleotide delivery for collagen VI- related congenital muscular dystrophy. Therapeutic Innovation Networks Pilot Data Scheme 拢10,000. 2023-2024. (PI Aguti, Zhou and Muntoni co-investigator).
Patents 2023-2024:
- Therapeutic molecules. Filing date: 17 May 2024. Application number: PCT/GB2024/051297
- Oligonucleotides for treating neuromuscular diseases. Filing date: 27 June 2023. Application number: EP23382654.4
Publications 2023-2024:
- Sara Aguti, Fady Guirguis, Carsten Bonnemann, Francesco Muntoni, Veronique Bolduc and Haiyan Zhou. Exon-Skipping for COL6A1 Mutation in Ullrich CMD. Methods in Molecular Biology, 2023; 2587:387-407.
- Foley et al. The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy.
- Sara Aguti, Shuzhi Cheng, Pierpaolo Ala, Sean Briggs, Francesco Muntoni, Haiyan Zhou. Strategies to improve the design of gapmer antisense oligonucleotide on allele-specific silencing. Molecular Therapy Nucleic acid, 2024. (Under final revision).
- Drop in Sessions
The centre runs regular surgeries to support researchers interested in developing or involved in AAV听or RNA therapie projects.听Location: QSH, please contact Dr Jo Ng on j.ng@ucl.ac.uk or Dr Sara Aguti on s.aguti@ucl.ac.uk to schedule a meeting.
Dr Jo Ng runs听regular surgeries to support researchers interested in developing or involved in AAV gene therapy projects. Jo has led preclinical AAV gene therapy projects in childhood neurological disorders. These have resulted in patent award, collaboration with industry partners, 听licensing agreements, orphan drug designation and clinical trial application. Her experience may help researchers consider translational aspects in AAV capsid selection, construct design, vector production, experimental design for preclinical efficacy and safety studies, approach to novel IP etc.听
Dr听Sara Aguti听has experience in developing RNA therapies for childhood neuromuscular disorders using various approaches (ASO, siRNA and saRNA). Currently, her primary focus is on generating peptide-targeted delivery strategies for various cells and tissues to address the challenges associated with in vivo delivery. Sara will be conducting regular surgeries to support researchers in the design, development, and in vivo RNA therapy delivery. She will assist in the following areas.听Mutation Suitability Assessment: Evaluating the suitability of specific mutations for the development of RNA therapies.听Oligo Sequence Optimization: Optimizing oligonucleotide sequences to improve their efficiency and specificity through chemical modifications and the study of target RNA secondary structures.听
