Horizon has exclusively licensed and will be implementing novel inventions from Dr. Hendrickson’s laboratory that will yield at least a 10-fold increase in the gene-editing frequency of its rAAV GENESIS™ platform technology. Horizon will also be funding continued research in the Hendrickson laboratory to bring ever greater enhancements to gene-editing in human cells. The current invention will enable Horizon to rapidly expand its panel of genetically-defined and patient-relevant X-MAN™ (gene-X; Mutant And Normal) disease models; and thus be better placed to decipher the ever increasing rate of human genetic variations being discovered.
At the heart of the GENESIS platform is the use of rAAV vectors that have a unique and powerful property in performing accurate and efficient gene-editing functions in human cells by exploiting homologous recombination (HR). HR is one of many mechanisms in a cell that can repair errors in DNA. When harnessed using rAAV gene-editing vectors, HR allows the precise alteration of any DNA sequence, permitting the correction of genetic defects in gene therapy applications, or the accurate modeling of genetic diseases in human cells when used in vitro.
rAAV vectors are 1000x more efficient than conventional plasmid techniques1, which have commonly been used to create transgenic mice, but are too inefficient to commercially engineer human cells. The Hendrickson laboratory discovered that shutting off an error-prone DNA repair mechanism called “non-homologous end joining” (NHEJ), which competes with HR, results in a 10-30 fold increase in the rAAV gene editing frequency in human cells. The exclusive licensing agreement involves a patented extension of this published2 discovery that uses a key practical enhancement in the form of a transient, chemical-mediated method to achieve a routine 10-fold increase in the gene-editing efficiency of Horizon’s rAAV GENESIS technology.
Commenting on the license agreement, Dr. Chris Torrance, CEO and co-founder of Horizon said: “rAAV gene-editing is currently the most accurate, flexible and cost-effective gene-editing technology. Increasing the efficiency of rAAV GENESIS, using Professor Hendrickson's discovery, will enable us to rapidly model the increasing array of genetic variations that are now known in human populations and linked to diseases such as cancer. Horizon and its rapidly growing network of academic rAAV-collaborators will use this advance to increase our current bank of 300+ disease models, to a resource comprising thousands of genetically-defined human cell-lines that can be used to elucidate and support all aspects of the development of novel personalized medicines“.
Professor Eric Hendrickson, said: “As a proof of principle, we demonstrated in 2008 that the inactivation of a non-homologous end joining gene, Ku70, resulted in higher absolute frequencies of rAAV-mediated gene edting.2 In the subsequent two years, we have identified other NHEJ and HR genes that similarly increase the frequency of rAAV-mediated gene editing. Importantly, the expression of some of these genes can be modulated with small molecule inhibitors. Thus we believe that the use of these small molecule inhibitors in combination with the already potent rAAV X-MAN methodology should result in the rapid development of new somatic cell models of human disease.”
Dr. Darrin M Disley, Executive Chairman of Horizon, said: “I am delighted that we have been able to expand our relationship with Professor Hendrickson. His curiosity as to how Horizon’s rAAV gene-editing technology works, when scientific logic suggests it should not, is a real example of how academic research can lead to both significant enhancement in general scientific knowledge as well as the improvement of an industrial manufacturing process like ours. The promise of the in-licensed inventions to give us an order of magnitude improvement to our rAAV platform is huge and will allow us to reduce manufacturing costs by 75% and development timelines by half for generating complex human models of diseases such as cancer by exquisitely and precisely altering human cellular genomes.”
The perpetuity license includes Horizon paying UMN up-front and milestone fees and an ongoing royalty on product sales once the inventions are commercially implemented. The sponsored research program is for an initial period of two years and will involve Horizon paying UMN $400,000 in fees.
1) Russell DW & Hirata RK, Human gene targeting using viral vectors. Nature Genetics, 18: 325-330 (1998).
2) Fattah F et al, Ku70, an essential gene, modulates the frequency of
rAAV-mediated gene targeting in human somatic cells. PNAS 105: 8703-8708 (2008).