Periodic Reporting for period 3 - AMELIE (Anchored Muscle cELls for IncontinencE)
Período documentado: 2023-09-01 hasta 2025-02-28
Faecal incontinence (FI) is a common condition affecting ~9% European adults (~67M people). Whilst not life threatening, it is classified as a disease by the WHO that seriously impairs daily living and productivity of affected individuals and their families, resulting in a substantial burden on European health services. FI following childbirth occurs in ~1 in 20 women, which means >200,000 women each year in EU could benefit from a regenerative medicine approach.
To date, regenerative medicine for FI using a patient’s own muscle cells has been constrained by sub-optimal manufacturing techniques. The techniques involved may damage the cells resulting in reduced effectiveness.
To address this, AMELIE is developing a radical, innovative approach to manufacture and deliver muscle cells into the body that may provide a more effective approach for regenerative medicine therapies for FI and other clinical indications. We are developing a novel product that comprises attaching the cells to implantable microspheres that eventually degrade in the body. This will increase survival of the cells during manufacture and delivery, increasing the likelihood of a clinical benefit.
To develop the new implantable microcarrier technology for use in regenerative medicine, AMELIE has the following objectives:
1. Establish new robust processes for the scalable manufacture, characterization, transportation and delivery of the implantable cell-microcarrier combination investigational product.
2. Demonstrate safety of the implantable cell-microcarrier combination investigational product using non-clinical testing to comply with national regulatory requirements and create an investigational medicinal product dossier that will enable evaluation of the technology across Europe.
3. Conduct a pan-European multi-centre clinical trial to primarily determine safety of the implantable cell-microcarrier combination when implanted into patients with FI.
4. Involve national and regional FI societies, patient support networks and the public throughout the project to establish suitable two-way channels for PPI activity and dissemination of project developments to patients, general public and scientific community.
5. Develop a business plan and future commercialisation strategy to enable patient access to the implantable cell-microcarrier combination across Europe and the World.
To date, regenerative medicine for FI using a patient’s own muscle cells has been constrained by sub-optimal manufacturing techniques. The techniques involved may damage the cells resulting in reduced effectiveness.
To address this, AMELIE is developing a radical, innovative approach to manufacture and deliver muscle cells into the body that may provide a more effective approach for regenerative medicine therapies for FI and other clinical indications. We are developing a novel product that comprises attaching the cells to implantable microspheres that eventually degrade in the body. This will increase survival of the cells during manufacture and delivery, increasing the likelihood of a clinical benefit.
To develop the new implantable microcarrier technology for use in regenerative medicine, AMELIE has the following objectives:
1. Establish new robust processes for the scalable manufacture, characterization, transportation and delivery of the implantable cell-microcarrier combination investigational product.
2. Demonstrate safety of the implantable cell-microcarrier combination investigational product using non-clinical testing to comply with national regulatory requirements and create an investigational medicinal product dossier that will enable evaluation of the technology across Europe.
3. Conduct a pan-European multi-centre clinical trial to primarily determine safety of the implantable cell-microcarrier combination when implanted into patients with FI.
4. Involve national and regional FI societies, patient support networks and the public throughout the project to establish suitable two-way channels for PPI activity and dissemination of project developments to patients, general public and scientific community.
5. Develop a business plan and future commercialisation strategy to enable patient access to the implantable cell-microcarrier combination across Europe and the World.
WP2:
• Appointment of subcontractor to produce TIPS microcarriers suitable for clinical use, and technical transfer of the manufacturing process from UCL.
• Supply of research grade TIPS microcarriers to AMELIE partners.
• Scaled-up process and production of engineering, pre-clinical and clinical batches of microcarriers that meet specifications.
• Comprehensive set of SOPs for manufacturing TIPS microcarriers.
• Verification of product performance characteristics of the TIPS microcarriers with conformity to set specifications.
WP3:
• Establishment of scalable, robust process for the manufacture of SMDC attached to TIPS microcarriers.
• Validation of xenogeneic(xeno)-free culture for the cell-microcarrier combination and of single-use stirred bioreactor vessels to prepare the cell-microcarrier combination.
• Successful expansion of SMDC using commercially available microcarriers and scalable culture systems;
• Manuscript under preparation for submission to Skeletal Muscle (BMC).
WP4:
• Identification of a carrier vehicle composition compatible for mixing the microcarriers into a suspension while in the syringe, validation of process to homegenously mix the microcarriers with attached cells in the carrier vehicle.
• Verified integrity of the product while in storage simulating transportation to the clinical sites.
• Verified cellular stability of product when attached to the microcarriers.
• Manufacturing protocol for the final product.
• Validation of transport system, and safety and in vitro stability analysis of the final product. Main techniques used: cell counting and viability using the NC200 system, analysis of myogenic capacity (by solf-agar), analysis of cell membrane markers by flow cytometry and epigenetic analysis of cells by karyotyping and CGH-Arrays.
• Onboarding of alternative courier for shipment of the final product able to provide assurance of delivery of product within its shelf-life, requiring a redesign of the final product secondary packaging boxes, with completion of dummy run to Madrid and set-up of a project-specific mailbox for placing AMELIE shipment requests.
WP5:
• Sub-contract a CRO for the pre-clinical testing.
• Studies completed to demonstrate the final product has an acceptable safety profile to progress to First-in-Human studies, with no significant safety concerns. Upon receipt of the final report from CRL, technical documents required by regulators can be completed and submitted.
WP6:
• Engaged with Regulatory Authorities to ensure proposed non-clinical safety data pack is suitable for regulatory compliance and query classification of the control intervention.
• Preparation of CIP and other patient-facing documents for the clinical trial.
• Clinical trial design adapted to variable duration follow-up to maximise data acquisition.
• Trial protocol finalised, ahead of Competent Authority submissions.
• Clinical trial application in UK granted;
• Priority case report forms (CRFs) created, and database underway.
WP7:
• Pan-European PPI survey in conjunction with national charity collaborators to investigate public perception of incontinence and the technology implantable cell-microcarrier across the European populace.
• Presentation at conference ICS 2022: “Cell Shape Characteristics of Human Skeletal Muscle Cells as a Predictor of Myogenic Competency: A New Paradigm Towards Precision Cell Therapy for Incontinence" (also published).
• Attended a national parliamentary meeting on continence care.
• Social media content with over 12,000 views.
• Produced lay language resources to deepen public knowledge of the AMELIE project.
• Article titled “Regenerative treatment may offer a cure for incontinence patients” published in a supplement in The Guardian, a national newspaper read across the UK – the digital version of the article had 126,504 impressions, 1,812 post engagements, and 1,739 click throughs when shared on the BRUK Facebook page
WP8:
• Evaluation of the IPR landscape and the incontinence market potential: Identification of potential routes to market + Initiation of the business case.
• Setup of the exploitation board.
• Appointment of subcontractor to produce TIPS microcarriers suitable for clinical use, and technical transfer of the manufacturing process from UCL.
• Supply of research grade TIPS microcarriers to AMELIE partners.
• Scaled-up process and production of engineering, pre-clinical and clinical batches of microcarriers that meet specifications.
• Comprehensive set of SOPs for manufacturing TIPS microcarriers.
• Verification of product performance characteristics of the TIPS microcarriers with conformity to set specifications.
WP3:
• Establishment of scalable, robust process for the manufacture of SMDC attached to TIPS microcarriers.
• Validation of xenogeneic(xeno)-free culture for the cell-microcarrier combination and of single-use stirred bioreactor vessels to prepare the cell-microcarrier combination.
• Successful expansion of SMDC using commercially available microcarriers and scalable culture systems;
• Manuscript under preparation for submission to Skeletal Muscle (BMC).
WP4:
• Identification of a carrier vehicle composition compatible for mixing the microcarriers into a suspension while in the syringe, validation of process to homegenously mix the microcarriers with attached cells in the carrier vehicle.
• Verified integrity of the product while in storage simulating transportation to the clinical sites.
• Verified cellular stability of product when attached to the microcarriers.
• Manufacturing protocol for the final product.
• Validation of transport system, and safety and in vitro stability analysis of the final product. Main techniques used: cell counting and viability using the NC200 system, analysis of myogenic capacity (by solf-agar), analysis of cell membrane markers by flow cytometry and epigenetic analysis of cells by karyotyping and CGH-Arrays.
• Onboarding of alternative courier for shipment of the final product able to provide assurance of delivery of product within its shelf-life, requiring a redesign of the final product secondary packaging boxes, with completion of dummy run to Madrid and set-up of a project-specific mailbox for placing AMELIE shipment requests.
WP5:
• Sub-contract a CRO for the pre-clinical testing.
• Studies completed to demonstrate the final product has an acceptable safety profile to progress to First-in-Human studies, with no significant safety concerns. Upon receipt of the final report from CRL, technical documents required by regulators can be completed and submitted.
WP6:
• Engaged with Regulatory Authorities to ensure proposed non-clinical safety data pack is suitable for regulatory compliance and query classification of the control intervention.
• Preparation of CIP and other patient-facing documents for the clinical trial.
• Clinical trial design adapted to variable duration follow-up to maximise data acquisition.
• Trial protocol finalised, ahead of Competent Authority submissions.
• Clinical trial application in UK granted;
• Priority case report forms (CRFs) created, and database underway.
WP7:
• Pan-European PPI survey in conjunction with national charity collaborators to investigate public perception of incontinence and the technology implantable cell-microcarrier across the European populace.
• Presentation at conference ICS 2022: “Cell Shape Characteristics of Human Skeletal Muscle Cells as a Predictor of Myogenic Competency: A New Paradigm Towards Precision Cell Therapy for Incontinence" (also published).
• Attended a national parliamentary meeting on continence care.
• Social media content with over 12,000 views.
• Produced lay language resources to deepen public knowledge of the AMELIE project.
• Article titled “Regenerative treatment may offer a cure for incontinence patients” published in a supplement in The Guardian, a national newspaper read across the UK – the digital version of the article had 126,504 impressions, 1,812 post engagements, and 1,739 click throughs when shared on the BRUK Facebook page
WP8:
• Evaluation of the IPR landscape and the incontinence market potential: Identification of potential routes to market + Initiation of the business case.
• Setup of the exploitation board.
QMUL, RU and UCL have contributed to a study investigating the use of cell shape characteristics as a novel profiling tool intended to identify which patients are likely to respond well to regenerative therapies. The study has evaluated the utility of multi-parametric imaging-based phenotypic characterization to distinguish the myogenic potency of SMDC. Heterogeneity in the formation of myotubes from different donors was correlated with cell shape descriptors. The results indicate that monitoring of cell shape during the early stages of bioprocessing using real-time imaging could be used to predict cellular competency necessary for differentiation and myofibre formation in vivo. This could help with selection of either patients or cell populations likely to yield better clinical outcomes in cell-based therapy for incontinence, making these therapies more cost effective (research paper published in Journal of Tissue Engineering and presented at ICS 2022).