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Horizon Discovery

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Sequencing DNA and using genetics Horizon can support the development of personalised medicines

Genome Editing
Translational genomics has become vital in the effort to drive personalized medicine, and the generation of precisely engineered cell lines and in vivo models is helping to lead the way. By editing the code of the human genome in functional human cells, the effects of genetic variation found in real patients can be reproduced in a laboratory setting, letting researchers ask important biological questions much earlier in the drug discovery process.Initial attempts to engineer genomes used homologous recombination (the cell’s natural DNA repair mechanism) in order to generate transgenic mice. This approach, which worked in mice, wasn’t effective for the development of somatic cell lines due to the very low rates of homologous recombination in these cells, so alternatives were needed.
Isogenic Cell Lines
Since then, tremendous research efforts have gone into the identifying and refining tools to generate engineered somatic cell lines. These fall into two categories based on the cellular mechanism they take advantage of:
Genome engineering through homologous recombination (e.g. rAAV), which takes advantage of a cell’s natural DNA repair mechanism through DNA crossover events to perform precise genome alterations through highly targeted insertions.
Genome engineering through double strand DNA break repair (e.g. ZFN), which generate a cut in DNA, after which a cell’s natural DNA repair mechanisms (non-homologous end joining) fix the break, during which errors can occur (leading to a knockout) or modified sequence can be introduced (knockin).
Each of these approaches has its own features and strengths and it is these differences are that make each best suited for addressing different gene-editing challenges. For this reason, Horizon has taken a ‘technology agnostic’ approach, developing deep experience and taking multiple licenses for rAAV, CRISPR and ZFNs, letting choose the right approach for any project, and letting us generate virtually any genomic modification with excellent precision and efficiency.
The Power of Engineered Cellular Disease Models
One illustrative example of the power of precisely engineered cell lines involves Iressa® (gefitinib). It was found through the course of its clinical development that only 4.8% of lung cancer patients – those with specific EGFR mutations – responded to Iressa therapy. Looking retrospectively, it was demonstrated using Horizon’s isogenic cell line pairs that EGFR mutant cells blinded amongst a broader panel of cells (EGFR wild type, K-Ras, B-Raf, PI3K) could predict the patient sub-groups who would respond or be resistant to Iressa therapy.Another example is Erbitux® (cetuximab), a drug for the treatment of metastatic colon cancer. It has been shown that 40% of patients have a mutant K-Ras gene and these individuals are known to be ‘non-responders’. Currently, all patients with these mutations are being excluded from therapy. There are many different variants of mutant K-Ras however, and in a subsequent study published in JAMA in 2010, Horizon cell lines predicted not all variants are equal and that there are patients who could benefit from Erbitux treatment who are excluded under current drug administration guidelines.

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