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Biocompatible nanoparticles for T cell targeted siRNA delivery as novel asthma therapy

Objective

The aim of this proposal is to engineer biocompatible nanoparticles that deliver short interfering RNA (siRNA) to activated T cells (ATCs) for the downregulation of the Type 2 T helper cell (Th2) transcription factor GATA-3. By downregulating GATA-3 with siRNA, which regulates the secretion of proinflammatory cytokines in chronic inflammatory diseases such as asthma, the activation of their downstream inflammatory cascades can be prevented. However, T cells are hard-to-transfect cells which are not readily accessible for nucleic acid based therapeutics. I am the first to have demonstrated successful and targeted siRNA delivery to ATCs ex vivo and in vivo for specific GATA-3 knockdown without delivering siRNA to naive T cells. Thus, I can avoid general immune suppression. This was achieved by engineering targeted siRNA delivery systems based on low molecular weight polyethylenimine (LMW-PEI) which form nanoparticles with siRNA and successfully deliver the latter to ATCs. The targeting approach was realized by coupling transferrin to LMW-PEI and by optimizing the coupling chemistry. I have demonstrated specific delivery to ATCs in a mouse model of allergic asthma and have screened siRNA sequences for efficient GATA-3 knockdown. The nanoparticles were administered locally to the lung to prevent the first-pass effect in the liver. The LMW-PEI based nanocarriers were very well tolerated in healthy animals, however, potentially caused additional proinflammatory effects in the asthma model.
Therefore, I will engineer nanocarriers that do not only specifically deliver siRNA to ATCs but are also biocompatible in a diseased state of the lung. I will use oligospermines, which are tetramers and octamers of spermine, an endogenous polyamine, and apply the optimized coupling strategy to target the spermine based nanocarriers to ATCs for therapeutic GATA-3 knockdown. To obtain clinically relevant formulations, I will produce inhalable powders of these nanocarriers.

Host institution

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Net EU contribution
€ 2 000 000,00
Address
Geschwister Scholl Platz 1
80539 Muenchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00

Beneficiaries (1)

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany
Net EU contribution
€ 2 000 000,00
Address
Geschwister Scholl Platz 1
80539 Muenchen

See on map

Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00