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GENESIS of gene editing
CAMBRIDGE, EnglandóHorizon Discovery, a company that provides research tools to support the development of personalized medicines, has entered into a collaboration for gene editing at the Institute of Neurology at the University College London (UCL) . The research program will focus on the creation of human isogenic disease model cell lines with insertion of Huntington's disease-causing triplet repeats.
Horizon will provide access to and training for its GENESIS gene editing technology as well as ongoing support during the creation of the cell lines. GENESIS is Horizon's genome-editing technology that uses adeno- associated virus (AAV) homologous recombination vectors (comprising single-stranded homologous DNA and not requiring double-strand breaks). GENESIS uses recombinant adeno-associated virus (rAAV) to induce homologous recombination in human somatic cells, allowing the site-specific precise modification of a cell's genome.
Using AAV to initiate homologous recombination, any sequence alterations contained within the homologous DNA are recombined with high precision into the target gene. This method has the ability to alter genomes in human somatic cell lines with 1,000 times more efficiency than plasmid-based methods.
The UCL collaboration will complement the GENESIS Gene Editing Consortium, which includes the National Cancer Institute, Cambridge University, Yale University and Dana-Farber Cancer Institute.
"Horizon will help UCL use the technology to create pairs of mutant and normal cell lines; the normal cell line will contain a normal number of triplet repeats, and we will create an allelic series with increased numbers of triplet repeats that are found in patients," explains Dr. Rob Howes, a principal scientist at Horizon. "The program at UCL represents a new disease area for Horizon, and the insertion of triplet repeats into a wild-type genome is a novel genetic alteration application for the GENESIS technology."
Sarah Tabrizi, a professor of clinical neurology at the UCL Institute of Neurology, a principal investigator of the TRACK-HD study and leader of all UCL Huntington's disease projects, adds: "Although mouse models have given important insights, it is important when studying human disease to use a broad approach, including cultured cells. The ability to accurately introduce the triplet repeat mutation into human somatic cell lines offers exciting possibilities in the study of Huntington's disease and potential therapies."
TRACK-HD was a multisite international study that aimed to establish what measurements were the best to use as "outcome measures" for clinical trials in Huntington's disease. It was funded by the CHDI Foundation and led by Tabrizi at UCL.
The results of TRACK-HD were recently published in The Lancet Neurology in an article titled, "Potential endpoints for clinical trials in pre-manifest and early Huntington's disease in the TRACK-HD study: Analysis of 24-month observational data." The article proposes a toolkit of outcome measurements, including optimized MRI brain scan measures and cognitive tests, to help make clinical trials in early manifest HD more efficient and more effective. Many drugs are in development for HD, and a major problem has been a lack of biomarkers to help decide whether a drug works or not.
"TRACK-HD has successfully identified biomarkers that it is hoped will achieve that aim, bringing clinical trials and effective treatments for HD closer. Longitudinal data from TRACK-HD may also help to inform early intervention strategies for other neurodegenerative disorders for which no highly predictive tests for pre-manifest disease stages are available," Howes states. "The use of patient-relevant disease models created by Horizon's rAAV-mediated genome editing technology is well established in oncology. We believe that by developing the application of this technology to other disease areas such as Huntington's disease, we can provide a vital tool for understanding, preventing and treating those diseases."
The new human isogenic cell lines generated by UCL will be exclusively licensed to Horizon. Horizon will also have an exclusive option to license new intellectual property that is developed. This forms part of Horizon's strategy to generate at least 2,500 new X-MAN (gene X- Mutant And Normal) models of cancer and neurodegenerative and cardiovascular disease.
"Creating this number of X-MAN models will address all of the main genetic variations associated with these diseases and provide valuable disease models for future drug discovery," Howes says.
The models will support drug discovery researchers in their efforts to understand how complex genetic diseases manifest themselves in real patients and help rationalize many aspects of drug development, with the goal of reducing the cost of bringing to market new personalized therapies.