Stephen Hart, PhD

Genetic therapies require a means of delivery of the therapeutic gene or oligonucleotide to cells of the affected tissue and this is perhaps the most important barrier to overcome in the development of gene-based therapies.

Viral vectors are widely used and have had some major clinical successes but for some applications their immunogenicity limits their effectiveness for applications where repeated in vivo delivery is required. Thus, we have focused on the use of non-viral formulations since these are less immunogenic, have a wide range of packaging capacities, are safer than viruses and are more easily produced in scales required for clinical uses.

In our group we are developing multifunctional nanoparticles termed Receptor-Targeted Nanocomplexes (RTN) comprising mixtures of cationic liposomes (L) and cationic targeting peptides (P) which self-assemble, electrostatically on mixing with DNA (D) or siRNA (R). RTN formulations comprise a peptide, P, which packages nucleic acids through a cationic K16 motif and targets receptors through short peptide ligands such as RGD integrin-targeting motifs (Tagalakis et al., 2011). The liposome component of the RTN includes a neutral lipid, DOPE, which enhances transfection by destabilising the endosomal bilayer allowing releasing the nucleic acid into the cytoplasm after endocytic uptake of the nanocomplexes and before endosomal degradation can occur.

Peptide and lipid chemistry allows a wide range of functionalities to be incorporated into the nanocomplexes so that these formulations increasingly resemble artificial viruses in their abilities to overcome cellular barriers to transfection.

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ASGCT 24th Annual Meeting

May 11-14, 2021

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