NEWS OF THE W EEK
EASIER ROUTE TO GENOMIC CHANGES
The researchers designed zinc finger nucleases that target specific genomic sequences in human embryonic kidney cells. The nucleases create DNA doublestrand breaks that then induce cellular DNA-repair mechanisms to create duplications or inversions at the sites. Sequence translocations have been achieved this way before, but “we are the first to demonstrate that zinc finger nucleases can be used to induce duplications and inversions,” Kim says. He and his coworkers detected, isolated, and characterized those variations. They also demonstrated that their nucleases could reverse the abnormal genomic inversion associated with hemophilia A. They believe the technique could eventually be used to correct genomic aberrations in pluripotent stem cells of patients. Once corrected, the cells could then
GENETIC ENGINEERING: Zinc finger
nucleases induce duplications, inversions of DNA sequences
for the first time that zinc finger nucleases can trigger sequence duplications and inversions at specific sites in living cells’ chromosomes. The researchers also engineered variations that corrected disease-associated genetic defects. The technique could be used in gene therapy applications and in studies of how genomic variations affect the function of live cells or organisms. Genomic variations such as deleted segments, duplicate sequences, and inversions (sequence reversals) often have significant effects on the health of cells and organisms. For example, DNA inversions cause almost half of severe hemophilia A cases. But in many instances the variations’ consequences are poorly understood, in part because researchers lack simple, effective techniques to engineer them into specific genomic sites. Existing methods either introduce changes only at random sites or require laborious premanipulation of genomic sequences in cells, which also leaves behind undesired foreign sequence elements in the genome. Now, associate professor of chemistry Jin-Soo Kim and coworkers at Seoul National University have used zinc finger nucleases—synthetic DNA-cleaving enzymes made from zinc-coordinating protein motifs— to create such variations more easily (Genome Res., DOI: 10.1101/gr.129635.111).
COURTESY OF JIN-SOO KIM
A
RESEARCH GROUP in South Korea has shown
be differentiated into appropriate types of somatic cells and reintroduced into patients. “Perhaps the most intriguing aspect of this study is the ability to generate individual structural variations at will so their biological consequences can be studied,” says biochemistry and molecular biology professor John H. Wilson of Baylor College of Medicine, who specializes in targeted genome modification. The new approach “should provide a useful gateway for such studies.” The technique also “potentially allows for the reversal of some [sequence] rearrangements in patients,” although “application to patients will require surmounting other substantial obstacles,” Wilson notes.—STU
Zinc finger nucleases (scissors) make breaks in genomic doublestranded DNA that cells then repair to create duplications (left) and inversions (right).
BORMAN
PHARMACEUTICALS Year ends with a flurry of oncology research pacts The year 2011 ended with multiple acquisitions and research partnerships through which the drug majors Takeda Pharmaceutical, Merck & Co., Eli Lilly & Co., and AstraZeneca gain access to compounds that biotech firms are developing for the treatment of cancer. Takeda announced that it will acquire Intellikine, a California-based smallmolecule drug discovery firm that is developing two new compounds that target the cancer-connected PI3 kinase/mTOR pathway. The Japanese firm will pay $190 million up front and up to $120 million in milestone payments.
In a deal aimed at the same pathway, Merck and Exelixis signed a licensing agreement under which Merck will pay $12 million up front for worldwide rights to Exelixis’ PI3K-delta R&D program, including XL499, its most advanced preclinical PI3K-delta inhibitor. Exelixis is eligible for up to $239 million in milestone payments. Lilly, meanwhile, will obtain exclusive licenses to ImmunoGen technology allowing Lilly to develop antibody-drug conjugates that link its own monoclonal antibodies with cytotoxic maytansinoids. Lilly will pay $20 million up front, with down-
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stream payments of up to $200 million. And AstraZeneca signed a pact with China’s Hutchison MediPharma, a subsidiary of Chi-Med, to develop volitinib, an inhibitor of the c-Met receptor tyrosine kinase. The U.K. drug company will pay $20 million up front and potential milestone payments totaling $120 million. For AstraZeneca, the agreement with Hutchison follows an acknowledgment that its investigational compound olaparib will not progress to Phase II development for treatment of serous ovarian cancer. The setback will result in a pretax charge of $285 million.—RICK MULLIN
