Measuring Potency of Cell and Gene Therapy Products
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The last decade has seen a rapid development in cell and gene therapies (CGT), which now offer promising solutions for diseases that couldn’t be adequately treated by traditional pharmaceuticals. Potency assays that measure the product-specific biological activity in a disease-relevant system are required by regulatory agencies to grant approval to CGT products.
What is cell and gene therapy?
CGT are composed of a diverse group of medicinal products. Cell therapies (including ex vivo gene therapies) involve the transfer of cells with a relevant function into the patient. Cells can have different origins, i.e., human (autologous or allogeneic), different differentiation stages, i.e., stem cells or differentiated cells, and can be genetically modified to exert the intended therapeutic effect. In genetically modified cell therapy, a functional transgene is transfected into cells ex vivo using viral (for example, lentiviruses) or nonviral (e.g., electroporation) vectors. Next, the modified cells are administered to the patient where the transgene will promote a therapeutic effect. Examples of these therapies include chimeric antigen receptor (CAR) T cells and genetically modified human stem cells (HSCs).
Gene therapies, in turn, involve the direct administration of genetic material into the patient to regulate or modify the genes of somatic cells in situ. Gene therapies generally target well-characterized genetic diseases. Gene augmentation therapies aim to replace a missing or aberrant protein within the cell to modulate the disease state. In this case, the transgene typically contains a DNA sequence that needs to be transcribed into mRNA and translated into a functional protein. In gene-silencing gene therapies, the transgene expresses a small RNA (for example, microRNA or small interfering RNA) that reduces the expression of an endogenous gene in the target cells to modulate the disease state. The therapeutic transgene can be delivered to the patient using different viral vectors such as adeno-associated viruses (AAVs) or nonviral vectors, such as lipid nanoparticles. An example of gene therapy is gene replacement for spinal muscular atrophy.
Why is it important to measure potency?
As with all pharmaceuticals, CGT products must meet rigorous safety guidelines to ensure their efficiency and safety. Potency assays for CGT products should measure molecular, biochemical, immunologic, phenotypic, physical, and biological characteristics as well as the relevant therapeutic activity or intended biological effect of the product or mechanism of action (MOA). Importantly, CGT products are complex and may rely on two or more MOAs, in which case each of these must be individually measured. Potency assays can be either in vitro or in vivo tests and are essential during multiple stages of the product life cycle, from early development to clinical trials. Potency assays are required for lot release testing, to show conformation testing, comparability studies, and stability testing. These tests are used to demonstrate that only products that meet these standards will be used during all phases of clinical investigation and following market approval.