Gene therapy is a transformational technology that promises new innovative medicines to prevent or treat inheritable diseases and those associated with aging. In vivo gene therapy using Adeno-associated Virus (AAV) vectors is one of the fastest growing sectors of the gene therapy market. The UK has established itself as the world’s leading cluster for these technologies, outside of the USA, with a vibrant academic pipeline and an industry of developers and manufacturers, which has been recognised in the UK government’s Life Science Vision. The gene therapy field was valued at USD 3.61 billion in 2019 and is projected to reach USD 35.67 billion by 2027. With this increase there will be a requirement for increased regulation of products. To assure rapid authorisation and availability of new life-changing medicines requires fast and robust mechanisms for comparing products, which biological standardisation can provide.
The AAV vector community currently relies upon AAV reference material produced over a decade ago and this supply is rapidly depleting. To address the challenge faced globally by this sector, scientists specialising in biological standards and control at the Medicines and Healthcare products Regulatory Agency (MHRA) and the Cell and Gene Therapy Catapult (CGT Catapult) have demonstrated, through manufacture and coordinated analysis at multiple international centres, that there is a requirement for development in the field of AAVassociated standards.
The World Health Organisation (WHO) Expert Committee on Biological Standards (ECBS) has highlighted the requirement for global convergence in standardisation of gene therapy products. The UK is also ideally placed to address the challenges of AAV standardisation as it has delivered 12% of all global trials for innovative cell and gene therapies. Demonstrating consistent purity is a critical quality control measurement for complex gene therapies and the field has developed, and continues to develop, various analytical methods to measure and assess this. As a result there exists no common benchmark, are therefore being used to determine the quality of AAV products leading to little or no comparability between these products. This lack of analytical standardisation makes it difficult to accurately compare data between different products, product batches and between different manufacturing sites which can contribute to variability in product quality and a potential impact on public health. Providing materials that enable the standardisation of AAV measurement will help address this challenge.
During this 6-month project colleagues at the CGTC and MHRA have worked together to manufacture and characterise an AAV reference material for coordinated analysis at multiple centres. The material produced is currently under evaluation by multiple centres internationally and data gathered will support future standardisation of AAV products. NIBSC Standards, from the MHRA, currently provide over 95% of the WHOs reference standard materials including a reference material for lentiviral-based gene therapies. This project will allow the MHRA to grow its organisational capabilities and offering for the growing international AAV industry and therefore maintaining the UK as a world leader in this area.
The funding provided by the Regulators Pioneer fund provided an opportunity to move into this area of research not currently addressed by scientific programmes at the MHRA and to link with CGT Catapult. The CGT Catapult has extensive experience and expertise in the production of AAV particles. This knowledge and manufacturing process has recently been established at the newly opened CGTC Manufacturing Innovation Centre in Braintree. This process was used to generate exemplar batches of AAV serotype 2 (AAV2) material, containing the gene encoding green fluorescent protein (GFP), which is a detectable protein commonly used as a representative gene in non-clinical systems. AAV2 was chosen as it is the most widely use serotype in clinical studies. The AAV2 particles containing the GFP gene can be purified to a relatively high specification in readiness for analytical assessment.
The material was supplied to scientists at the MHRA who performed analytics such as Enzyme-linked Immunosorbent Assay (ELISA), Electron microscopy (EM) and Polymerase chain reaction (PCR) to further evaluate the material. This material also underwent freeze drying under different conditions to evaluate its stability, as freeze drying enables the material to be distributed more easily as a cold chain does not need to be maintained.
The materials are currently being distributed to international external collaborators such as academic laboratories and industrial stakeholders to evaluate its ‘fitness for use’ as an analytical reference material and evaluate freeze drying as a possible stabilising method for AAVs.
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