rAAV-ing up the stem cell engine

Horizon Discovery, University of Washington collaborating to apply rAAV gene editing in inducible human pluripotent stem cells

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CAMBRIDGE. U.K.—Horizon Discovery and the University of Washington (UW) recently announced a two-year research collaboration aimed at generating a process for gene editing in inducible human pluripotent stem cells.

The research will exploit the efficiency and accuracy of recombinant Adeno-Associated Virus (rAAV) gene editing vectors to enable the future creation of thousands of new X-MAN (gene-X; mutant and normal) cell models, among the world's first sources of genetically-defined and patient-relevant human cell lines.
As part of the collaboration, Horizon will fund a two-year, $400,000 research program at the university and will have an exclusive right to any new intellectual property created.

The research program—which will be led by UW Professor David Russell, the inventor of rAAV gene editing, who has already demonstrated the concept of targeting human pluripotent stem cells—will enable the generation of diverse arrays of tissue-derived disease models for personalized medicine R&D applications, as well as optimized reagents for the production of biological drugs/materials and ex-vivo-derived tissue therapies.

"The aim is to build on Professor Russell's publication in the Journal of Molecular Therapeutics in 2010, which showed the ability of rAAV gene editing vectors to successfully target human pluripotent stem cells to create a routine process for generating new human isogenic cell lines in a wide range of tissue types and that address a range of disease areas of interest to pharmaceutical and diagnostic research," Dr. Chris Torrance, CSO at Horizon, tells ddn. "These disease models will be marketed under the X-MAN brand and the new rAAV GENESIS+ method marketed as a means to develop any type of genetically defined human cell line."

Moreover, the Horizon-UW collaboration follows an agreement signed in April 2009, in which the UW granted Horizon an exclusive worldwide license to its patent suite and know-how relating to the use of parvoviral vectors in human gene editing for in-vitro human cell-lines and stem cell applications. That agreement came on the heels of a previous deal, inked in 2008, in which UW granted Horizon exclusive worldwide licenses for all pharmaceutical, diagnostic and bioproduction applications across all therapeutics fields of use.

Torrance notes it has been more than a decade since Russell developed rAAV as a putative means of performing more efficient gene therapy in humans. 

"Horizon has since adapted this technology to provide a wide array of genetically defined in-vitro disease models to support basic research and drug discovery efforts," Torrance says. "It is a natural progression to now continue this relationship to explore how rAAV can be brought into routine use with hES cells."

According to Torrance, Horizon has been working with Russell on the design, development and improvement of rAAV gene editing vectors as a means of engineering the genome of normal and disease human cell types. The company is the exclusive worldwide license holder of Russell's rAAV inventions for all pharmaceutical, diagnostic and bio-production applications across all therapeutics fields of use.

Torrance explains that a focus of the collaboration is to "generate several different iPS cell-lines harboring key cancer associated genetic alterations, as a proof-of-concept for using this system to model, or even correct ex vivo (with subsequent transplantation into patients) genetic diseases in stem cells."  

Torrance also points out that there are clear advantages to the application of rAAV gene editing to inducible human pluripotent stem cells.

"Genome editing in human cells, including stem cells, has not been historically an easy thing to do," he explains. "rAAV is far more efficient at hijacking a high-fidelity DNA repair mechanism (homologous recombination), to precisely insert, delete or substitute target DNA sequences, than older or alternative genome editing techniques. rAAV may enable clean and reproducible genome editing in stem cells to become a reality, as well as providing a rapid source of accurate disease models that can be differentiated from these iPS cell-lines into disease relevant tissue types." 

Dr. Darrin M. Disley, executive chairman of Horizon, explains that his company's relationship with the University of Washington is a central force in the development of the company.

"The new agreements will further align the technical and commercial interests of Horizon and UW," he says. "The ability to precisely and stably alter the genome of mammalian (and especially human) cell lines, without introducing errors or exogenous vector sequences, will open up multiple-new opportunities for our products and services in pharmaceutical and diagnostic development, as well as bioproduction markets. This latter field has long been subject to compromises in the long-term stability and yield of bioexpressed products and the genetic stability inherent in stem cells promises big advances in this field."

Measuring success of the collaboration, Torrance notes that there are a range of different types of disease model being generated, such as gain-of-function point mutations that represent targets for therapy, signaling pathway reporters and target gene-amplifications. 

"We expect one and probably several of these applications will be successful and if this is the case, we will build upon this POC stage and integrate these applications into our commercial pipeline," he concludes.

Horizon was founded in 2007 by Torrance and Prof. Alberto Bardelli. With headquarters in Cambridge, U.K., the company builds on a long heritage in gene engineering, cancer research and translational medicine, and draws on intellectual property and know-how from the University of Washington, the Johns Hopkins University, the University of Maryland, the University of Minnesota and the Department of Oncological Sciences at the University of Torino Medical School.

The University of Washington Center for Commercialization is producing innovations from biofuel alternatives, to more effective treatments for Alzheimer's disease and brain cancer, to purification technology for drinking water in the developing world.

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