Periodic Reporting for period 3 - ARDAT (Accelerating Research & Development for Advanced Therapies)
Berichtszeitraum: 2022-11-01 bis 2023-10-31
Curative or near curative therapies for Rare and Orphan Diseases have been a long-held desire for both patients and many in the biomedical research and development arena. Rare diseases are often very severe, genetically driven illnesses with high morbidity and mortality that place a large burden on families of patients and healthcare systems. Though these diseases are relatively rare the costs of medicines are high, even for the many that provide only marginal benefit. Gene and cell therapies provide an opportunity for a curative, single treatment for many of these devastating diseases, eliminating the need for chronic treatment. The goal of gene and cell therapy is to provide, with a single treatment, sustained therapeutic levels of transgene expression or cell activity, potentially of life-long duration. There are several significant challenges to this goal in the form of the substantial gaps in our understanding of immunological and non-immunological factors that may impact on persistent expression and eligibility for treatment. ARDAT brings together a ‘best-with-best’ multidisciplinary team of leading international academic, industry and EFPIA groups with complimentary expertise in vector design, gene therapy, immunology, AAV biology, chemistry, engineering, biotechnology, omics, drug safety, viral vector production, regulatory processes, and clinical trials. All have a compelling track record in the field of advanced therapies and are committed to bring about significant advances in the treatment of rare diseases.
The overall objective of ARDAT is to develop and provide the data and tools to fill gaps in our knowledgebase in the areas of immunology and metabolism of viral gene/cell therapy to accelerate the research and development of Advanced Therapy Medicinal Products (ATMPs). This will involve the development of data and tools for gene and cell therapy, to provide developers and regulators with the information they need to move these potentially transformative medicines forward more swiftly and to patients in need
The overall objective of ARDAT is to develop and provide the data and tools to fill gaps in our knowledgebase in the areas of immunology and metabolism of viral gene/cell therapy to accelerate the research and development of Advanced Therapy Medicinal Products (ATMPs). This will involve the development of data and tools for gene and cell therapy, to provide developers and regulators with the information they need to move these potentially transformative medicines forward more swiftly and to patients in need
Notable progress has been made over the first 3 periods
Work Package 1: Establishment of management and reporting structures.
Work Package 2:
Completed assessment of the effects of rAAV9 transduction in terms of (a) modulation of gene expression of a panel of neuroinflammatory genes; and (b) remodelling of the secretory profile of the iNeurospheroid cultures, analysing several pro-inflammatory proteins and chemokines shown to be implicated in neuroinflammation.
Establishment of methods to determine T cell polyfunctionality from in vivo and 3D models using IsoLight technology and comparison with CyTOF. A proof-of-concept is completed and methodology will now be applied in 3D and mouse models.
An abstract summarizing the thus far collected data was submitted to the European Society of Gene and Cell Therapy meeting 2023 in Brussels. Data are currently being written into manuscript format and will likely be submitted by Q1 2024, for joint scientific publication. Despite small delays, the project is on track. In the next 12 months the focus will be on finishing the polyfunctional T cell analysis using samples available in house. In addition, the second focus will be on collaborations within WP2.4 and WP2.2 aiding 3D cell culture system research.
Work package 3:
Analytical assays for product characterisation have been developed and transfered from the UK based CRO Cell and Gene Therapy Catapult to the consortium.
Significant progress under Task 3.2.1 “Metabolism of the therapeutic vector genome in different cell types We have further improved our pipeline for data analysis resulting from ITR sequencing in AAV genomes by Oxford Nanopore sequencing.
Work package 4:
Completion of laboratory manual to establish standard operating procedures for sample handling and storage along with oversight from the Biorepository Governance Board.
Agreements between Partner Organisations for sample transfer in and out of the ARDAT biorepository are complete, allowing transfer of the first samples in Q1 2023
Establishment of a full battery of sample testing requirements and matching this with the assay capability across the consortium.
Signed material and data transfer agreement for the transfer of the samples to the ARDAT biobank. PFE, ULIV and USFD have signed this agreement.
Work package 5:
Comprehensive literature reviews in immunosuppression and pre-clinical protocols
Discussions with regulatory bodies to prepare the way for development of new treatments.
Two databases supporting the biodistribution/shedding whitepaper and another to support the ongoing immunogenicity and immunosuppression whitepaper. This will lead to the establishment of a comprehensive database for the curation and analysis of data generated from the project and to facilitate data-driven support e.g. guidance on clinical trial design, leveraging of information to waive nonclinical studies in certain situations, prediction of the consequences of pre-existing immunity and / or immune responses induced by a particular product, support for regulatory interactions beyond the duration of the project.
A Regulatory landscape assessment was published in April 2022.
A regulatory landscape survey was piloted at ESGCT in October 2022. it was shared with WP5 partners and results collated and discussed. Subsequently, the survey was shared internally within the consortium where it is hoped to canvas more academic partners.
Work Package 1: Establishment of management and reporting structures.
Work Package 2:
Completed assessment of the effects of rAAV9 transduction in terms of (a) modulation of gene expression of a panel of neuroinflammatory genes; and (b) remodelling of the secretory profile of the iNeurospheroid cultures, analysing several pro-inflammatory proteins and chemokines shown to be implicated in neuroinflammation.
Establishment of methods to determine T cell polyfunctionality from in vivo and 3D models using IsoLight technology and comparison with CyTOF. A proof-of-concept is completed and methodology will now be applied in 3D and mouse models.
An abstract summarizing the thus far collected data was submitted to the European Society of Gene and Cell Therapy meeting 2023 in Brussels. Data are currently being written into manuscript format and will likely be submitted by Q1 2024, for joint scientific publication. Despite small delays, the project is on track. In the next 12 months the focus will be on finishing the polyfunctional T cell analysis using samples available in house. In addition, the second focus will be on collaborations within WP2.4 and WP2.2 aiding 3D cell culture system research.
Work package 3:
Analytical assays for product characterisation have been developed and transfered from the UK based CRO Cell and Gene Therapy Catapult to the consortium.
Significant progress under Task 3.2.1 “Metabolism of the therapeutic vector genome in different cell types We have further improved our pipeline for data analysis resulting from ITR sequencing in AAV genomes by Oxford Nanopore sequencing.
Work package 4:
Completion of laboratory manual to establish standard operating procedures for sample handling and storage along with oversight from the Biorepository Governance Board.
Agreements between Partner Organisations for sample transfer in and out of the ARDAT biorepository are complete, allowing transfer of the first samples in Q1 2023
Establishment of a full battery of sample testing requirements and matching this with the assay capability across the consortium.
Signed material and data transfer agreement for the transfer of the samples to the ARDAT biobank. PFE, ULIV and USFD have signed this agreement.
Work package 5:
Comprehensive literature reviews in immunosuppression and pre-clinical protocols
Discussions with regulatory bodies to prepare the way for development of new treatments.
Two databases supporting the biodistribution/shedding whitepaper and another to support the ongoing immunogenicity and immunosuppression whitepaper. This will lead to the establishment of a comprehensive database for the curation and analysis of data generated from the project and to facilitate data-driven support e.g. guidance on clinical trial design, leveraging of information to waive nonclinical studies in certain situations, prediction of the consequences of pre-existing immunity and / or immune responses induced by a particular product, support for regulatory interactions beyond the duration of the project.
A Regulatory landscape assessment was published in April 2022.
A regulatory landscape survey was piloted at ESGCT in October 2022. it was shared with WP5 partners and results collated and discussed. Subsequently, the survey was shared internally within the consortium where it is hoped to canvas more academic partners.
Corresponding to key challenges of advancing highly specific ATMPs towards clinical trials for rare disorders, ARDAT will create an IT-driven R&D characterization platform, including: i) a rationally stratified biobank with biosamples from healthy volunteers and patients dosed with cell and gene therapies from broad geographic areas; ii) a rationally designed and aligned platform of assays and models for immunogenicity, safety and efficacy testing of ATMPs; iii) a curated database and IT infrastructure containing all in-house data on safety and efficacy of ATMPs. Through the assessment of immunological and non-immunological factors influencing safety and efficacy of ATMPs, ARDAT will foster the development of disease-modifying ATMPs in the setting of personalized medicine. The consortium will efficiently share and transfer key materials, rationally stratified clinical samples, vectors, standardisation assays, protocols, data and know-how between laboratories, maximising the chances of translating the ATMPs from bench to bedside and providing data to support regulatory filings and to address regulatory and safety concerns. Hence, the outcome will be more than the sum of our respective areas of expertise, workforce and the respective local academic and industrial environments. The multidisciplinarity of our consortium and close alignment between public and EFPIA partners enhances the chance of successful achievements of the ARDAT objectives. The immediate potential impact on both the academic and industrial research domains aimed at developing disease-modifying treatments for severe, genetically driven rare diseases justifies accepting the challenges inherent in this work. The success of this consortium will increase Europe’s industrial competitiveness and leadership in the areas of cell / gene therapies for rare diseases, where the expectations for innovative and efficacious therapeutic approaches are high.