Delivery of peptide responsive gene vectors with receptor targeted nanocomplexes
Lead Research Organisation:
University College London
Department Name: Cell and Developmental Biology
Abstract
This project is a combination of gene therapy and nanotechnology with the aim of delivering gene therapeutics in a targeted and responsive manner. A PCR assembly approach will be used to generate synthetic promoters that are activated by the environment of inflammation through responsiveness to hypoxia and inflammatory mediators. As an alternative approach therapeutic molecules will be expressed from chemically-modified mRNA (cmRNA) which is a recently described non-viral vector. Mini circle DNA with responsive promoters and cmRNA will be delivered to target cells (synoviocytes and angiogenic endothelium) with peptide targeted nanocomplexes in vitro and in vivo in gene therapy studies.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009513/1 | 01/10/2015 | 31/03/2024 | |||
| 1905921 | Studentship | BB/M009513/1 | 01/10/2017 | 30/01/2022 | Emily Young |
| Title | Targeted non-viral gene delivery for rheumatoid arthritis |
| Description | Receptor targeted nanoparticles (RTNs) have previously been developed by our lab group (Hart group) to effectively deliver plasmid DNA, mRNA and siRNA in vitro and in vivo [1-6]. These RTNs comprise a cationic lipid that self-assembles with the anionic DNA backbone and a neutral lipid DOPE to aid DNA endosomal escape. In addition, formulations include a peptide containing a cationic, 16-lysine domain for electrostatic DNA packaging and a targeting ligand, separated by a cleavable or hydrophobic linker to alter RTN stability. This project is developing RTNs that selectively deliver plasmid DNA to the inflamed synovium with the aims of producing a therapy for rheumatoid arthritis that has improved efficacy at the site of the disease and reduced systemic side-effects. Incorporating a synoviocyte targeting peptide into RTNs has demonstrated selectivity for synoviocytes in vitro and may therefore provide a novel method for targeted gene delivery to the synovium. Optimisation and evaluation of the synoviocyte targeting RTNs is ongoing. 1. Manunta, M.D., et al., Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis. Sci Rep, 2017. 7(1): p. 700. 2. Fernando, O., et al., Development of Targeted siRNA Nanocomplexes to Prevent Fibrosis in Experimental Glaucoma Filtration Surgery. Mol Ther, 2018. 26(12): p. 2812-2822. 3. Tagalakis, A.D., et al., Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung. Thorax, 2018. 73(9): p. 847. 4. Yu-Wai-Man, C., et al., Receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient delivery system for MRTF silencing in conjunctival fibrosis. Scientific Reports, 2016. 6: p. 21881. 5. Tagalakis, A.D., et al., A Receptor-targeted Nanocomplex Vector System Optimized for Respiratory Gene Transfer. Molecular Therapy, 2008. 16(5): p. 907-915. 6. Munye, M.M., et al., Role of liposome and peptide in the synergistic enhancement of transfection with a lipopolyplex vector. Sci Rep, 2015. 5: p. 9292. |
| Type | Therapeutic Intervention - Cellular and gene therapies |
| Current Stage Of Development | Initial development |
| Year Development Stage Completed | 2019 |
| Development Status | Under active development/distribution |
| Impact | NA |