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Name of Submitter:
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Catherine Dulac
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Title of proposed idea:
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Novel technology to generate fast, efficient and muti-gene (>3) targeting and KOs
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What is the major obstacle/challenge in the biomedical research field? What is needed to overcome this obstacle/challenge?
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Ongoing genome-wide studies in large cohorts of patients and in experimental animal systems are uncovering a large numbers of disease susceptibility factors. However promising these factors may seem individually, they are likely to act in combination with each other, rather than alone. To test hypotheses about pathology, diagnostic, and treatments, associated with these multigenic features, one must be able to generate animal systems in which multiple genes have been deleted or modified. As of today, the current state of knockout, knockdown, and otherwise transgenic or gene targeting modifications enable to perform single gene modifications, and at most double or triple modifications by crossing animals in which single genes have been targeted. Further, knock down agents such as shRNAs are toxic when used in large combinations, and do not work equally well in all tissues. The obtention of double mutants resulting from the cross of 2 lines of genetically modified mice is very inefficient, long and costly, and establishing triple KOs is viewed as heroic and in practice rarely done. An ideal technology would enable to generate triple, quadruple, quintuple, etc.. mutants fast and efficiently.
To reach this goal, the steps leading to classical gene targeting must be re-thought in order to identify short cuts in the process of generating genetically modified animals and enable the simultaneous introduction in a cell to be targeted of a large number of modifying constructs at once. |
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What emerging scientific opportunity is ripe for investment by the Common Fund?
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A number of exciting new technologies have recently been reported in the literature that could nucleate and inspire further improvements and innovations: TALEN gene targeting could presumably lead to multi-gene targeting, and haploid stem cells can help skip a step in the long process of traditional gene targeting. There might be other ideas in the work. |
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What are the potential Common Fund investments that could accelerate scientific progress in this field?
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Common Fund Investments could lead to specific projects aimed at developing techniques for fast and multi-gene (3 and above) targeting in the mouse or any other genetically amenable experimental system. |
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If a Common Fund program on this topic achieved its objectives, what would be the impact?
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The impacts would be multiple and large:
- traditional gene modifications would be made faster and more efficient, thus saving a lot of money to investigators and funding agencies.
- model systems in which combinations of multiple risk factors are introduced could now be generated, thus offering a new set of opportunities for studying and curing disease in all fields of biology (cancer, mental disorders, metabolic disorders, you name it...) |
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