GENESIS of gene editing

Horizon Discovery and UCL Institute of Neurology collaborate in rAAV-mediated genome editing

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CAMBRIDGE, England—Horizon Discovery, a company thatprovides research tools to support the development of personalized medicines,has entered into a collaboration for gene editing at the Institute of Neurologyat the University College London (UCL). The research program will focus on thecreation of human isogenic disease model cell lines with insertion ofHuntington's disease-causing triplet repeats.
Horizon will provide access to and training for its GENESISgene editing technology as well as ongoing support during the creation of thecell lines. GENESIS is Horizon's genome-editing technology that usesadeno-associated virus (AAV) homologous recombination vectors (comprisingsingle-stranded homologous DNA and not requiring double-strand breaks). GENESISuses recombinant adeno-associated virus (rAAV) to induce homologousrecombination in human somatic cells, allowing the site-specific precisemodification of a cell's genome.

Using AAV to initiate homologous recombination, any sequence alterationscontained within the homologous DNA are recombined with high precision into thetarget gene. This method has the ability to alter genomes in human somatic celllines with 1,000 times more efficiency than plasmid-based methods.
The UCL collaboration will complement the GENESIS GeneEditing Consortium, which includes the National Cancer Institute, CambridgeUniversity, Yale University and Dana-Farber Cancer Institute.

"Horizon will help UCL use the technology to create pairs of mutant and normalcell lines; the normal cell line will contain a normal number of tripletrepeats, and we will create an allelic series with increased numbers of tripletrepeats that are found in patients," explains Dr. Rob Howes, a principalscientist at Horizon. "The program at UCL represents a new disease area forHorizon, and the insertion of triplet repeats into a wild-type genome is anovel genetic alteration application for the GENESIS technology."

Sarah Tabrizi, a professor of clinical neurology at the UCL Institute ofNeurology, a principal investigator of the TRACK-HD study and leader of all UCLHuntington's disease projects, adds: "Although mouse models have givenimportant insights, it is important when studying human disease to use a broadapproach, including cultured cells. The ability to accurately introduce thetriplet repeat mutation into human somatic cell lines offers excitingpossibilities in the study of Huntington's disease and potential therapies."

TRACK-HD was a multisite international study that aimed to establish whatmeasurements were the best to use as "outcome measures" for clinical trials inHuntington's disease. It was funded by the CHDI Foundation and led by Tabriziat UCL.

The results of TRACK-HD were recently published in The Lancet Neurology in an article titled, "Potential endpoints forclinical trials in pre-manifest and early Huntington's disease in the TRACK-HDstudy: Analysis of 24-month observational data." The article proposes a toolkitof outcome measurements, including optimized MRI brain scan measures andcognitive tests, to help make clinical trials in early manifest HD moreefficient and more effective. Many drugs are in development for HD, and a majorproblem has been a lack of biomarkers to help decide whether a drug works ornot.

"TRACK-HD has successfully identified biomarkers that it is hoped will achievethat aim, bringing clinical trials and effective treatments for HD closer.Longitudinal data from TRACK-HD may also help to inform early interventionstrategies for other neurodegenerative disorders for which no highly predictivetests for pre-manifest disease stages are available," Howes states. "The use ofpatient-relevant disease models created by Horizon's rAAV-mediated genomeediting technology is well established in oncology.  We believe that by developing the application of thistechnology to other disease areas such as Huntington's disease, we can providea vital tool for understanding, preventing and treating those diseases."

The new human isogenic cell lines generated by UCL will be exclusively licensedto Horizon. Horizon will also have an exclusive option to license newintellectual property that is developed. This forms part of Horizon's strategyto generate at least 2,500 new X-MAN (gene X- Mutant And Normal) models ofcancer and neurodegenerative and cardiovascular disease.

"Creating this number of X-MAN models will address all of the main geneticvariations associated with these diseases and provide valuable disease modelsfor future drug discovery," Howes says.
The models will support drug discovery researchers in their efforts tounderstand how complex genetic diseases manifest themselves in real patientsand help rationalize many aspects of drug development, with the goal ofreducing the cost of bringing to market new personalized therapies.

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