Periodic Reporting for period 1 - INSPIRE (Developing novel inhaled bioengineered Extracellular Vesicle RNA based advanced therapeutics, delivered by tailored aerosol delivery technology for the treatment of lung cancer)
Période du rapport: 2022-06-01 au 2023-11-30
Solution:
Delivery is a major barrier to successful pulmonary gene therapy for competing viral and non-viral gene transfer vectors and the vast promise of gene therapy has many challenges to overcome. OMNI's novel solution is pioneering the use of genetically modified MSC EVs with a proprietary surface engineering technology to further enhance delivery through the mucus barrier and into the targeted lung cells. This platform technology also combines efficient aerosol delivery of the EVs via AERO's proprietary state-of-the-art vibrating mesh nebulizer technology. This unique solution solves the problems associated with lung-targeted delivery of RNA-based advanced therapies.
Innovation:
INSPIRE has assembled pan-European innovation across many disciplines – EV-related production and therapeutic technologies (OMNI); manufacturing technologies (EVER); medical devices and state-of-the-art aerosol delivery technology (AERO); the enhanced screening and assay of the novel treatment will be enhanced by innovative screening and modelling technologies (RBIO, TCD, DKFZ). The assembled INSPIRE consortium believes that our proprietary, genetically modified stem cell EVs carrying highly-rational, well-researched RNA-based advanced therapeutic payloads, delivered primarily by the inhaled route of delivery, could lead to a breakthrough treatment for lung cancer globally. This project directly aligns with HORIZON-HLTH-2021-TOOL-06-02 in addressing RNA advanced therapeutics to treat high-burden diseases with unmet clinical need.
Partner roles:
OMNI: Lead optimisation of prototype product to TPP specification, selection of optimal bioengineered MSCs, surface-engineering (WP 3); Project and Innnovation management (WP 1); Commercialisation and regulatory communication (WP 2).
MYR: Financial management and EC-communication and reporting.
AERO: Aerosol device development and formulation.
TCD: In vitro development and optimisation of Air Liquid Interface tissue-cancer cell-immune cell co-culture models and ex-vivo organoid models from diverse lung cancer patient samples.
RBIO: EV therapeutic profiling at single cell level to assess the cell-kill effect of lung tumour cells in dissociated tumours and the response of immune cells using RBIO’s proprietary platform.
DKFZ: Murine in vivo investigation with state-of-the-art in vivo models with OS003 EVs/vehicle control administered by aerosol and IV.
EVER: Process development and CMC for scalable manufacturing of OS003 using GMP USP and DSP equipment relying on EVER's proprietary manufacturing platform based on a physically-triggered EV production.
CEBIOM: Develop physiomimetic 3D in vitro testing organoid platforms containing extracellular matrix to mimic the evolving mechanical properties of lung cancer, allowing analysis of relevant information about OS003 EVs performance under different lung cancer scenarios.
PLEx/BPEx: Guidance on strategic product development and regulatory consulting for advanced biopharmaceuticals including ATMPs (Cell & Gene Therapy products), stem cells and extracellular vesicles (EVs).
Project objectives:
Lung cancer (LC) treatments have advanced in recent years with the advent of genetic profiling and immunotherapy. However, LC is a complex heterogeneous disease and survival rates remain poor. RNA (mRNA, microRNA, other non-coding RNAs and nucleic acid-based modulators of the same) and gene therapies (DNA or gene editing) for delivering nucleic acid-based therapeutics have curative potential for a host of indications previously untreatable. They have yet to enter the mainstream, due to safety concerns and difficulties delivering them efficiently to areas other than the liver, kidney and circulatory system. Aerosol delivery allows direct targeting of lung tissues but viscous mucus in the lung is a significant barrier to gene transfer to the target cells of the lungs. Even if the mucus layer can be penetrated, inefficient penetration through the cell membrane further impedes access of these vectors to the underlying target cells, thus preventing successful gene transfer.
Delivery is a major barrier to successful pulmonary gene therapy for competing viral and non-viral gene transfer vectors and the vast promise of gene therapy has many challenges to overcome. OMNI's novel solution is pioneering the use of genetically modified MSC EVs with a proprietary surface engineering technology to further enhance delivery through the mucus barrier and into the targeted lung cells. This platform technology also combines efficient aerosol delivery of the EVs via AERO's proprietary state-of-the-art vibrating mesh nebulizer technology. This unique solution solves the problems associated with lung-targeted delivery of RNA-based advanced therapies. The ultimate objective is to develop off-the-shelf affordable treatment for lung cancer and that would be applicable to many other types of solid tumours.
Project endpoint:
The endpoint of INSPIRE is to advance the ATMP-device combination towards IND-enabled stage, and to delineate clinical and commercial stage GMP-stage manufacturing.
Delivery is a major barrier to successful pulmonary gene therapy for competing viral and non-viral gene transfer vectors and the vast promise of gene therapy has many challenges to overcome. OMNI's novel solution is pioneering the use of genetically modified MSC EVs with a proprietary surface engineering technology to further enhance delivery through the mucus barrier and into the targeted lung cells. This platform technology also combines efficient aerosol delivery of the EVs via AERO's proprietary state-of-the-art vibrating mesh nebulizer technology. This unique solution solves the problems associated with lung-targeted delivery of RNA-based advanced therapies.
Innovation:
INSPIRE has assembled pan-European innovation across many disciplines – EV-related production and therapeutic technologies (OMNI); manufacturing technologies (EVER); medical devices and state-of-the-art aerosol delivery technology (AERO); the enhanced screening and assay of the novel treatment will be enhanced by innovative screening and modelling technologies (RBIO, TCD, DKFZ). The assembled INSPIRE consortium believes that our proprietary, genetically modified stem cell EVs carrying highly-rational, well-researched RNA-based advanced therapeutic payloads, delivered primarily by the inhaled route of delivery, could lead to a breakthrough treatment for lung cancer globally. This project directly aligns with HORIZON-HLTH-2021-TOOL-06-02 in addressing RNA advanced therapeutics to treat high-burden diseases with unmet clinical need.
Partner roles:
OMNI: Lead optimisation of prototype product to TPP specification, selection of optimal bioengineered MSCs, surface-engineering (WP 3); Project and Innnovation management (WP 1); Commercialisation and regulatory communication (WP 2).
MYR: Financial management and EC-communication and reporting.
AERO: Aerosol device development and formulation.
TCD: In vitro development and optimisation of Air Liquid Interface tissue-cancer cell-immune cell co-culture models and ex-vivo organoid models from diverse lung cancer patient samples.
RBIO: EV therapeutic profiling at single cell level to assess the cell-kill effect of lung tumour cells in dissociated tumours and the response of immune cells using RBIO’s proprietary platform.
DKFZ: Murine in vivo investigation with state-of-the-art in vivo models with OS003 EVs/vehicle control administered by aerosol and IV.
EVER: Process development and CMC for scalable manufacturing of OS003 using GMP USP and DSP equipment relying on EVER's proprietary manufacturing platform based on a physically-triggered EV production.
CEBIOM: Develop physiomimetic 3D in vitro testing organoid platforms containing extracellular matrix to mimic the evolving mechanical properties of lung cancer, allowing analysis of relevant information about OS003 EVs performance under different lung cancer scenarios.
PLEx/BPEx: Guidance on strategic product development and regulatory consulting for advanced biopharmaceuticals including ATMPs (Cell & Gene Therapy products), stem cells and extracellular vesicles (EVs).
Project objectives:
Lung cancer (LC) treatments have advanced in recent years with the advent of genetic profiling and immunotherapy. However, LC is a complex heterogeneous disease and survival rates remain poor. RNA (mRNA, microRNA, other non-coding RNAs and nucleic acid-based modulators of the same) and gene therapies (DNA or gene editing) for delivering nucleic acid-based therapeutics have curative potential for a host of indications previously untreatable. They have yet to enter the mainstream, due to safety concerns and difficulties delivering them efficiently to areas other than the liver, kidney and circulatory system. Aerosol delivery allows direct targeting of lung tissues but viscous mucus in the lung is a significant barrier to gene transfer to the target cells of the lungs. Even if the mucus layer can be penetrated, inefficient penetration through the cell membrane further impedes access of these vectors to the underlying target cells, thus preventing successful gene transfer.
Delivery is a major barrier to successful pulmonary gene therapy for competing viral and non-viral gene transfer vectors and the vast promise of gene therapy has many challenges to overcome. OMNI's novel solution is pioneering the use of genetically modified MSC EVs with a proprietary surface engineering technology to further enhance delivery through the mucus barrier and into the targeted lung cells. This platform technology also combines efficient aerosol delivery of the EVs via AERO's proprietary state-of-the-art vibrating mesh nebulizer technology. This unique solution solves the problems associated with lung-targeted delivery of RNA-based advanced therapies. The ultimate objective is to develop off-the-shelf affordable treatment for lung cancer and that would be applicable to many other types of solid tumours.
Project endpoint:
The endpoint of INSPIRE is to advance the ATMP-device combination towards IND-enabled stage, and to delineate clinical and commercial stage GMP-stage manufacturing.
Summary of main technical/clinical achievements:
- Cell engineering work has been undertaken by OMNI to transduce cells to continually express therapeutic genes of interest (GOI), these cells will be used to produce OS003 as a novel MSC EV-based ATMP.
- Preliminary work on all the novel assays were initiated and progressed by relevant partners, with TCD having developed SOPs for the preclinical evaluation (efficacy screening); RBIO has started preliminary work towards this objective, specifically, INFf & Granzyme B assay development and optimization for single cell screening has started, with additional targets planned for development prior to final testing with OS003 EVs. Furthermore, a reference assay has been developed to ascertain platform performance and metrics accuracy.
- EV formulations available to date have been successfully nebulized using the Aerogen Solo device; additionally, a novel method of capturing EV aerosol has been designed and developed to aid in further screening once final EV formulation is available.
- Problems have been identified for resolution in cell engineering and production of EVs. The work program has been amended to address these in parallel to allow the project to progress on time once critical dependencies have been achieved.
- Cell engineering work has been undertaken by OMNI to transduce cells to continually express therapeutic genes of interest (GOI), these cells will be used to produce OS003 as a novel MSC EV-based ATMP.
- Preliminary work on all the novel assays were initiated and progressed by relevant partners, with TCD having developed SOPs for the preclinical evaluation (efficacy screening); RBIO has started preliminary work towards this objective, specifically, INFf & Granzyme B assay development and optimization for single cell screening has started, with additional targets planned for development prior to final testing with OS003 EVs. Furthermore, a reference assay has been developed to ascertain platform performance and metrics accuracy.
- EV formulations available to date have been successfully nebulized using the Aerogen Solo device; additionally, a novel method of capturing EV aerosol has been designed and developed to aid in further screening once final EV formulation is available.
- Problems have been identified for resolution in cell engineering and production of EVs. The work program has been amended to address these in parallel to allow the project to progress on time once critical dependencies have been achieved.
- Optimised the aerosolisation of EV formulation.
- Engineered cells to express anti-cancer payloads in the isolated EVs
- Engineered cells to express anti-cancer payloads in the isolated EVs