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22 | SEPTEMBER 1, 2016 | GENengnews.com | Genetic Engineering & Biotechnology News tained that his company has had a dozen de- veloped scaffolds with many compounds in the proprietary bank that are well character- ized and future candidates for trials. Aside from showing promise in the treat- ment of cardiovascular disease and cancer, the candidate inhibitors have demonstrated potential against many other diseases, such as chronic kidney disease and Alzheimer's dementia. The company receives solicitation calls ev- ery week from corporate or governmental in- stitutions such as the U.S. National Institute of Aging (NIA) for collaborating on projects, noted McCaffrey, adding that such collabo- ration proposals are encouraged since hav- ing a diversity of products and projects with widespread application potential requires specialized collaborators. The NIA is especially concerned with any drug that promises to lighten the societal bur- den that will be imposed by the dementia and debilitation caused by Alzheimer's disease, a threat that looms over an enlarged segment of the population. According to McCaffrey, Resverlogix' apabetalone, being a comple- ment cascade modulator and having inter- action with apolipoprotein A1, may have a two-prong beneficial action in early-onset Alzheimer's disease. Ewelina Kulikowski, Ph.D., serves as se- nior vp of R&D; at Resverlogix. When ques- tioned about any other epigenetic projects that may contribute to the understanding of syndromes, disorders, or perhaps nondisease subjects, as done with genomic investiga- tions, Dr. Kulikowski explained that it is well recognized that genetics and epigenetics play a role in various disorders and as the filed grows novel connections will be made. Moreover, in contrast to the genomic profile, epigenomic profiles are amenable to modification by not only direct pharmaco- logical methods, but also by environmental or other external factors such as pollution, stress, diet, or nutrition. These factors may tap into biochemical pathways and lead to epigenetic effects through methylation/de- methylation, or other means of marking of DNA, or through acetylation/deacetylation or writing/erasing of histones for subse- quent bromodomain reading and trancrip- tive regulation of genes. Dr. Kulikowski referred to the work of Craig B. Thompson, M.D., president and CEO of the Memorial Sloan Kettering Cancer Center. Dr. Thompson has a fo- cused project on the biochemical metabolic acetyl-CoA pathway-linked effects on the epigenome. The project encompasses the in- vestigation of underlying mechanisms, such as those involved in altering the availability acetyl-donor molecules for histone modifi- cation. An analogous glutamine metabol- ic pathway link for methyl-donor molecules has been explored for epigenetic methylation of DNA and histones. Dr. Kulikowski also alluded to an orphan disease project at the company as well as a proof-of-concept trial that could further characterize the role of epigenetics in modu- lating critical pathways underpinning a num- ber of rare diseases. Immuno-Oncology Developments Constellation Pharmaceuticals, primar- ily an oncology- and immuno-oncology- focused epigenetics company, has a BRD inhibitor, CPI-610, and an acetyltransferase targeted molecule, CPI-1205, in trials. Robert Sims, Ph.D., vice president of research, said that about eight other small molecules are in preclinical development. No neuroscience tar- get drugs are currently being researched, but targets in other areas are of interest. These include targets in virology, inflammation, and immunology. As for nondisease projects, Dr. Sims pointed out that Constellation has developed epigenetic data-collating tools for interroga- tion studies that are available as an outreach to the research community. With respect to proteomics, he said that the company has ex- pertise in histone proteomic analysis that has advanced its epigenetic biology knowledge base. He concurs that analysis by mass spec- trometry has limitations and shortcomings in tertiary and quaternary structure analysis of the bromodomain-bound histone subunit conformational changes with respect to bio- logical activity. When asked about future developments, Dr. Sims stated that the company's main objective and current mission is to develop small-molecule therapeutics. Constellation is a privately owned venture that has a good portfolio of backing investors and partners. This portfolio has continued to expand since Constellation's long-time partner, Genentech, ended a colloboration and backed out of an acquisition deal. There is no apparent consid- eration of a strategic merger or acquisition or public offering in the short term. Vendor Interest Top biotech supply vendors also have an eye on the fast-moving epigenetics field. Their goal has been to provide researchers with efficient time-saving kits and equip- ment dedicated to the relevant experimen- tal routines. PerkinElmer, for example, has a catalog of products ready for use as well as others in development. To keep apace of advances in epigenetics, the company has recruited specialized personnel from varied epigenetic research corporate or academic programs. The company anticipates that its experts, such as senior application scientist Daniel Cardillo, will leverage their familiarity with the experimental protocol literature to real- ize commercial vending opportunities. PerkinElmer has several histone-targeted assay kits. Some of them use homogeneous AlphaLISA for BRD4 and BRD2 binding and are useful for optimization investiga- tions of inhibitors. Cell-based assay kits are ready for sale and in development for bro- modomain protein readers. Epigentek and Zymo Research are among other vendors with strong portfolios of epi- genetic research tools and supplies. As has genomics, epigenetics and epig- enomics have shown a great deal of progress in a short time. These disciplines, however, also have become quite complex and com- plicated with the advent of new discoveries. One fact is certain. There is a deep and rich untapped resource of knowledge yet to be mined in these still young fields. Epigenetics Continued from page 20 OMICS > JAX Wins $28.3M from NIH for JAX Wins $28.3M from NIH for Knockout Mouse Project The Jackson Laboratory (JAX) won $28.3 million over five years from the NIH to fund the second phase of its Knockout Mouse Production and Phenotyping Project. JAX said the funding will enable it to use CRISPR/Cas9 gene editing to generate, breed, cryopreserve, and clinically assess the health and well- being of 1,000 lines of mice. For each of the new mouse lines, JAX said, it will assess body weight and composition, metabolic and physiological parameters, and behav- ioral and cognitive function at several age points. Both the mice and the resulting data will be made available to the worldwide scientific community prior to publication, JAX said, adding that researchers will work with the scientific community to select genes of excep- tional interest, genes for which little is currently known, and genes predicted to function in select pathways. > Editas Inks CRISPR Licensing Editas Inks CRISPR Licensing Deal with MGH Editas Medicine will license from Massachusetts General Hospital (MGH) intellectual property and tech- nology related to high-fidelity Cas9 nucleases and Cas9 protospacer adja- cent motif variants. The value of the licensing agree- ment was not disclosed by Editas, which said the deal will enable it to address an expanded range of geneti- cally defined diseases with potential for enhanced specificity. Editas is licensing technology developed by one of its scientific co-founders and consultants, J. Keith Joung, M.D., Ph.D. He also holds posi- tions at MGH as associate chief for research, and as the Jim and Ann Orr MGH research scholar in the hospital's Department of Pathology. > Repositive and AstraZeneca Ink PDX Collab AstraZeneca Ink PDX Collab Repositive, a software company that develops tools to improve access to human genomic research data, is launching a consortia project in col- laboration with AstraZeneca to de- velop a collaborative, precompetitive resource. The consortia project antici- pates that the resource will provide streamlined discovery and access to molecular data from patient-derived xenographs for use within oncology research. n News Genomics & Proteomics Global alterations in the DNA methylation status of the ge- nome correlate with various biological conditions, including development, aging and disease. Global hypomethylation of cytosines is a hallmark of cancer and primarily reflects the demethylation of DNA repetitive elements. "Likewise, global changes in the levels of the DNA meth- ylation variant, 5-hydroxymethylcytosine (5-hmC), serve as a prognostic indicator in certain cancers and neurodegen- erative disorders," said Johanna Samuelsson, Ph.D., senior research scientist at Active Motif. To better understand how changes in DNA modifications influence normal and diseased states, methods to accurately quantify global 5-methylcytosine (5-mC) and 5-hmC are highly warranted, she pointed out. Active Motif offers plate-based assays to perform com- parative studies of global changes in 5-mC and 5-hmC, ac- cording to Mabelle Ashe, Ph.D., marketing communications manager for the company. The firm's Global DNA Methylation–LINE-1 Kit measures methylation of a consensus sequence within the human re- petitive Long Interspersed Nucleotide Element 1 (LINE-1), a commonly used surrogate for global 5-mC levels, noted Dr. Ashe, adding that this technique provides a "simpler alterna- tive to traditional methods of quantifying global 5-mC levels. It has been used to perform correlative studies demonstrat- ing the role of epigenetic alterations in biological processes, such as in the development of colorectal cancer." Likewise, the Active Motif Global 5-hmC Quantification Kit enables researchers to correlate shifts in global 5-hmC levels with specific biological processes, she added. n Quantifying 5-mC and 5-hmC Global Levels