Genetic Engineering & Biotechnology News

DEC 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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8 | DECEMBER 2017 | B E S T O F C R I S P R 2 017 famous "brake" protein that keeps the immune system from attacking cancer cells. In the wake of this news, renowned cancer researcher Carl June, M.D., was quoted as say- ing, "I think this is going to trigger 'Sputnik 2.0,'" essentially, a duel between the U.S. and China. That race is heating up fast. New Scientist recently reported that "as many as 20 human trials" of CRISPR would soon be launched, mainly in China. Currently, nine trials of CRISPR- based therapeutics are listed on, although several are not yet recruiting. Nagging concerns remain, how- ever. Skeptics point to the potential for off-target effects (a recent paper in Nature Methods set off a signficant firestorm from leaders in the field), delivery challenges, the hurdles that are typical to any product undergoing regulatory review, and now some re- invigorated rival technologies. Sangamo, which has been devel- oping ZFN-based gene-editing tech- nology for more than 13 years, is still square in the game. The company has one product already in clinical trials and three more headed there. (See Sidebar, "Can Zinc Fingers Zip Along?") TALENs have also entered the clinic, at least in a 2015 "first in man" study of a single patient with B-cell acute lymphoblastic leukemia. More such trials are planned and Thermo Fisher Scientific recently relaunched TALENs as a genom- editing tool that "performs compa- rably or better than CRISPR." The company is "focusing on using them to edit parts of the genome where CRISPR is either inefficient or com- pletely nonfunctional." One major task will be tweaking CRISPR, or its competitors, to make them clinical-grade products. "A key step in going from the lab to a therapeutic is making a high-quality nuclease and qualifying its activity ➜ The first ever in vivo genome-editing trials are currently recruiting. Sangamo, which is sponsoring the trials, already has an anti-HIV gene-editing based product in trials, but that involves removing stem cells, editing them, and then returning them to the patient (i.e., ex vivo treatment). That treatment knocks out the CCR5 gene, thereby protecting cells against HIV infection. "Until now, gene editing has mostly focused on ex vivo approaches," said Michael Holmes, Sangamo's vice president of research. "We are now introducing nucleases into the body." Sangamo's approach uses zinc finger DNA- binding proteins (ZFPs) consist of a tandem array of zinc fingers, which are short peptides of 28 residues that rec- ognize three-to-four base pairs. With an attached nuclease, a ZFP can cut DNA, and either delete and/or add specific sequences. The company was founded in 1995 and launched its first HIV trials in 2009. But this year could be a major turning point for Sangamo's gene-editing program. One company-sponsored study will introduce a gene into the livers of hemophilia B patients. Since the liver nor- mally generates the clotting factor these patients need, the hope is that inserting the corrected gene will help prevent uncontrolled bleeding episodes. Sangamo is also trying this approach against Hurler and Hunter syndromes. Hurler syndrome is also known as mucopolysaccharidosis type I (MPS I) and is caused by an alpha-L-iduronidase deficiency. Hunter syndrome, mean- while, is also called mucopolysaccharidosis II (MPS II), and is a lysosomal storage disease caused by iduronate-2-sulfa- tase (I2S) deficiency. "What the field of gene editing has been doing—and Sangamo, in particular—is pushing the sensitivity of the assays used to assess off-target effects," explained Edward Rebar, vice president of technology at Sangamo. Several such assays are available and widely used, includ- ing GUIDE-Seq and CIRCLE-Seq. "As more therapies push toward the clinic, optimizing these become a priority," he added. In addition, the company has placed significant focus on improving the efficiencies of the nucleases they use, and optimizing delivery. Sangamo uses adeno-associ- ated virus (AAV ) serotype 6 vectors. It is also investigating lipid nanoparticulars, mRNA, and other forms of AAV. Naturally, Sangamo is also being strategic about which indications it tackles first. It started with the ex vivo ap- proaches, editing genes in T cells and stem cells. As the com- pany moves to in vivo gene editing, delivery will become a major focus. "Delivery is the challenge, but as we address that we will be able to reach more and more cell types," Holmes said. n Can Zinc Fingers Zip Along? While Many Companies Are Jumping on the CRISPR Gene-Editing Train, Sangamo Presses Ahead with Zinc Finger Proteins in Its Gene-Editing Program

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