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Biocompatible nanoparticles for T cell targeted siRNA delivery as novel asthma t...

Biocompatible nanoparticles for T cell targeted siRNA delivery as novel asthma therapy 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 do... see more

31/12/2021

LMU MUENCHEN

2M€

Project Budget: 2M€

Project leader

LUDWIGMAXIMILIANSUNIVERSITAET MUENCHEN No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

PARTICIPATION DEPralty Sin fecha límite de participación.

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Financing granted El organismo H2020 notifico la concesión del proyecto The day 2021-12-31

ERC-StG-2014: ERC Starting Grant Scope:Objectives

I+D

Cerrada does 11 years

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characteristics of the participant

Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

Private Information

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2 Participantes

LMU MUENCHEN

2.00M€ | Leader

FARELL INSTRUMENTS

257.24K€ | participant

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Project duration: 77 months Date Start: 2015-07-23
End date: 2021-12-31

Project leader

LUDWIGMAXIMILIANSUNIVERSITAET MUENCHEN No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Project Budget 2M€

participation deadline Sin fecha límite de participación.

Project description 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.

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