Periodic Reporting for period 4 - ARDAT (Accelerating Research & Development for Advanced Therapies)
Berichtszeitraum: 2023-11-01 bis 2024-10-31
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 4 periods
Work Package 1: Establishment of management and reporting structures.
Work Package 2:
Completed assessment of the effects of rAAV9 transduction formed the basis of D2.3.
Establishment of methods to determine T cell polyfunctionality from in vivo and 3D models produced the publication; doi:10.3389/fimmu.2024.1450524.
By using anti-IdeS mAbs generated by the consortium, quantitation of anti-IdeS IgG and IgA in the plasma & serum of healthy individuals was completed.
Work package 3:
Analytical assays for product characterisation have been developed & transferred from the UK based CRO Cell and Gene Therapy Catapult to the consortium.
Progress under Task 3.2.1 further improving our pipeline for data analysis resulting from ITR sequencing in AAV genomes by Oxford Nanopore sequencing.
Development of a pipeline to characterise the modification preferences of the current globalized editing methodology.
D3.1: “Identification of factors with key role in vector genome dilution in models of liver diseases” was submitted.
Cell line assays suggest the potential immune evasion ability of glyco-AAV9 vectors, next steps will extend into in vivo systems.
AAV9-based gene replacement for SPG47 resulted in several outputs; a publication; doi:10.1038/s44321-024-00148-5 patent filing, IND submitted to FDA and a start-up company (BlackfinBio).
Work package 4:
Completion of laboratory manual to establish procedures for sample handling and storage along with oversight from the Biorepository Governance Board.
Agreements between Partner Organisations for sample transfer in & out of the ARDAT biorepository completed, allowing the transfer of samples to the ARDAT Biobank.
Establishment of a full battery of sample testing requirements and matching this with the assay capability across the consortium.
PFE, ULIV and USFD signed MDTA for the transfer of samples to the ARDAT biobank.
Full ethical approval from the Health Research Authority (HRA) for the ARDAT Biobank at the USFD.
A review of current immunosuppressive protocols used in AAV gene therapy has been published; doi:10.1016/j.ymthe.2024.07.016.
Negotiations ongoing with the UK National Health Service (NHS) to secure patient samples from individuals treated with AAV9-based gene therapy, Zolgensma. Alongside accessing samples from patients treated with AAV5.
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 to support the 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.
A Regulatory landscape assessment was published in April 2022 and a regulatory landscape survey piloted at ESGCT in October 2022 this was shared with WP5 partners and results collated & discussed. Subsequently, the survey was shared internally to canvas more academic partners.
D5.13: "Whitepaper 2 (immunosuppression protocols)" was submitted. Cell Report Medicine has invited full paper for consideration.
Work Package 1: Establishment of management and reporting structures.
Work Package 2:
Completed assessment of the effects of rAAV9 transduction formed the basis of D2.3.
Establishment of methods to determine T cell polyfunctionality from in vivo and 3D models produced the publication; doi:10.3389/fimmu.2024.1450524.
By using anti-IdeS mAbs generated by the consortium, quantitation of anti-IdeS IgG and IgA in the plasma & serum of healthy individuals was completed.
Work package 3:
Analytical assays for product characterisation have been developed & transferred from the UK based CRO Cell and Gene Therapy Catapult to the consortium.
Progress under Task 3.2.1 further improving our pipeline for data analysis resulting from ITR sequencing in AAV genomes by Oxford Nanopore sequencing.
Development of a pipeline to characterise the modification preferences of the current globalized editing methodology.
D3.1: “Identification of factors with key role in vector genome dilution in models of liver diseases” was submitted.
Cell line assays suggest the potential immune evasion ability of glyco-AAV9 vectors, next steps will extend into in vivo systems.
AAV9-based gene replacement for SPG47 resulted in several outputs; a publication; doi:10.1038/s44321-024-00148-5 patent filing, IND submitted to FDA and a start-up company (BlackfinBio).
Work package 4:
Completion of laboratory manual to establish procedures for sample handling and storage along with oversight from the Biorepository Governance Board.
Agreements between Partner Organisations for sample transfer in & out of the ARDAT biorepository completed, allowing the transfer of samples to the ARDAT Biobank.
Establishment of a full battery of sample testing requirements and matching this with the assay capability across the consortium.
PFE, ULIV and USFD signed MDTA for the transfer of samples to the ARDAT biobank.
Full ethical approval from the Health Research Authority (HRA) for the ARDAT Biobank at the USFD.
A review of current immunosuppressive protocols used in AAV gene therapy has been published; doi:10.1016/j.ymthe.2024.07.016.
Negotiations ongoing with the UK National Health Service (NHS) to secure patient samples from individuals treated with AAV9-based gene therapy, Zolgensma. Alongside accessing samples from patients treated with AAV5.
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 to support the 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.
A Regulatory landscape assessment was published in April 2022 and a regulatory landscape survey piloted at ESGCT in October 2022 this was shared with WP5 partners and results collated & discussed. Subsequently, the survey was shared internally to canvas more academic partners.
D5.13: "Whitepaper 2 (immunosuppression protocols)" was submitted. Cell Report Medicine has invited full paper for consideration.
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.