Over the first five periods, Accelerating Research & Development for Advanced Therapies (ARDAT) has made substantial progress across all work packages:
Work Package 1:
Management and reporting structures were established, alongside communication assets developed to clearly convey the ARDAT mission, in collaboration with the Patient and Public Involvement and Engagement (PPIE) group.
Work Package 2:
Key scientific advances were achieved, including assessment of recombinant adeno-associated viruses (rAAV)9 transduction, development of methods to measure T cell polyfunctionality (resulting in a peer-reviewed publication doi:10.3389/fimmu.2024.1450524) and new insights into AAV immunogenicity in the liver and central nervous system (CNS). The consortium generated anti-IdeS monoclonal antibodies and quantified anti-IdeS antibodies in healthy individuals. Immune phenotyping and genotyping tools were also developed to better understand resistance to AAV transduction.
Work Package 3:
Analytical assays for gene therapy product characterization were developed and transferred within the consortium. Data analysis pipelines were established for AAV genome sequencing and gene editing characterization. Glyco-engineered AAV9 vectors with potential immune-evasion properties are being tested. Notably, an AAV9-based gene replacement therapy for SPG47 led to a publication, patent filing, Food and Drug Administration Investigational New Drug (FDA IND) clearance, and the launch of a start-up company (BlackfinBio).
Work Package 4:
A laboratory manual and governance framework for the ARDAT Biobank were completed, with ethical approval secured and agreements finalised for sample transfer. Standardised testing requirements and assay capabilities were aligned across partners. New AAV9 assays were developed and applied to patient samples across 2 independent sites. Longitudinal samples were collected from SMA patients treated with Zolgensma, and recruitment of Haemophilia B patients is underway. A review of immunosuppressive protocols in AAV gene therapy was also published doi:10.1016/j.ymthe.2024.07.016.
Work Package 5:
Extensive literature reviews (immunosuppression and pre-clinical protocols) and regulatory discussions have helped to prepare the way for future therapy development. Two databases were created to underpin whitepapers on biodistribution, immunogenicity, and immunosuppression, contributing to a comprehensive project-wide data resource. A regulatory landscape assessment and survey were conducted, culminating in a published review in Cell Reports Medicine on global immunogenicity and immunomodulation requirements for gene therapy development doi: 10.1016/j.xcrm.2025.102422.
Overall, ARDAT has delivered significant scientific, regulatory, infrastructural, and translational outputs, advancing the development of gene therapies for rare diseases.
