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European Biopharmaceutical Review

Modelling Genetic Disease: iPS Cell Line Development Using Gene Editing

The development of therapeutic treatments is a complex process linked to the ability to understand mechanisms underlying human disorders by studying them in human cell models. Patient-to-patient genetic diversity creates additional layers of technical complexity when making the leap to personalised medicine. Major advancements in pluripotent stem cell and CRISPR-Cas9 gene editing technologies have unlocked enormous potential in the generation of isogenic model cell lines, engineered to study a wide range of diseases in an increasing number of cell and tissue types derived from the pluripotent state. However, challenges remain as successful isolation of clonal human induced pluripotent stem (iPS) cell lines that are edited in a genetically precise, intended manner is notoriously difficult due to the hurdles of precision and efficiency. Fortunately, there is a growing body of available resources, methods, and services to support researchers in the development of human models of disease for basic research and screening studies.

Generating a Model of Genetic Disease

CRISPR-Cas9 has entered the vernacular with speed and influence, rivalled only by the impact this technology has had on the advancement of understanding cellular health and disease. Human diseases that arise from genetic abnormalities vary greatly in nature and scope. In one disease a single base change can be the difference between sickness and health, whereas in others, large insertions or deletions (INDELs) affect the phenotype. There are some diseases where it is thought that a combination of single nucleotide changes and/or INDELs spread across a gene – or genes – results in disease.

As the CRISPR-Cas9 toolbox has expanded, the ability to model more complicated genetic diseases has grown and the generation of cell models with multiple gene knockouts or larger INDELs is now possible. In fact, the generation of clonal iPS cell lines with specific point mutations, knockouts, conditional knock-outs or knock-ins, tagged proteins, translocations, and even genomic landing pads can be commercially provided (1). Base editing technologies have also developed over the last several years, but their editing window is limited to the four transition mutations (C→T, A→G, G→A and T→C). Though currently unable to make any combination of base-to-base change, this is an area of active study and innovation with rapid advances in technological development widening the scope of its potential (2).

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Amanda Haupt is a Senior Scientist and R&D Project Manager at Horizon Discovery, a PerkinElmer Company. During her years with the company she has contributed to the development of the broad portfolio of gene editing and gene modulation reagents. Today, Amanda works with cross-functional teams to launch innovative new products and services within the research reagents, cell line engineering, and screening divisions of Horizon Discovery. Before joining Horizon, Amanda worked at the Allen Institute for Cell Science in Seattle, WA where she contributed to the generation of the Allen Cell Collection of endogenously tagged iPS cell lines.
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