Genetic Engineering & Biotechnology News

JUL 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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16 | JULY 2017 | GENengnews.com | Genetic Engineering & Biotechnology News ple, one of our partner companies uses a pat- ented micromolded microplate to promote self-aggregation in cell cluster production. But no matter how the 3D spheroids are formed, automation is a critical workflow component. Automation increases through- put, streamlines workflows, enhances re- producibility, and decreases variability com- pared to manual methods. Additionally, reagent and material costs can be reduced when miniaturizing and au- tomating 3D methods, while minimal hands- on time frees users to focus on other labora- tory tasks. Finally, automation monitors and tracks the entire process from research and development, through scale up, and on to manufacturing. Dr. Guye A trend to monitor is the applica- tion of genetically engineered tissues and reporter cell lines, as well as tissues derived from human induced pluripotent stem cells. Although these models are promising, they are, in many cases, incapable of delivering adequate performance, for now. From the technology perspective, there are already many methods and technologies available to make 3D cell culture models to cover most organs in the body, and many of these models are tailored for use in distinct phases of drug development. The current technology, however, will not allow develop- ers to take full advantage of 3D models until it incorporates certain advances, such as microphysiological systems capable of interconnecting 3D models, more thorough pharmacological data, and implementation of clinically relevant biomarkers into assays adapted for use with advanced models. Dr. Kugelmeier Responding as the represen- tative of a company that is developing a novel 3D cell culture technology, my answer is bi- ased. But I am not alone in thinking that basic science has never been so close to realizing so many clinical applications. The current state of scientific and technological developments, especially with stem cells, inspires bold vi- sions about the future of medicine. Helping to realize the new clinical appli- cations are several "workhorse" technolo- gies. One of them, 3D cell culture, is effec- tively being harnessed now that the scalable production of sized, stem-cell-quality clus- ters is possible. Other workhorses include gene editing, extracellular matrix, single-cell- handling, and imaging technologies. Dr. Bulpin Genome-editing tools (such as CRISPR), 3D bioprinting, microfluidics, and imaging technologies are all advanc- ing rapidly and will likely have a signifi- cant impact on 3D cell culture in the near future. Dr. Joore I personally believe that organ- on-a-chip technology in combination with induced pluripotent stem cells, organoids, and CRISPR/Cas9 presents a tantalizing opportunity to generate complex biology, and cells carrying any genetic background may be used. Think about complex, in- tractable diseases such as central nervous system disease, neurodegenerative diseases, and cancer. Machine learning and artificial intelligence will be essential to analyzing the multifactorial output of such 3D, multicell- type models. And finally, we're working on novel ways to create even more physiologi- cally relevant models in the OrganoPlates ® by adding more tissue lanes, functionalities, and readouts. Ms. Floyd The development of new instru- ments that provide real-time imaging and plate-reading capabilities, such as the Incu- Cyte Live Cell System (Essen BioScience), will be largely enabling for 3D culture sys- tems. The ability to detect cell-specific mark- ers in mixed-cell populations will be particu- larly useful with 3D models. Finally, 3D bio- printing will drive research and discovery in new and exciting ways, allowing the creation of tissue and organs that will provide more biologically predictive models. Prof. Przyborski 3D cell culture is a tool that enables researchers to improve the growth and function of cells. It will play an impor- tant role in the creation of more sophisticat- ed tissue models that more accurately mimic tissue structure. 3D culture combined with other technologies, such as oxygen control and fluid flow, will enhance such models still further as surrogates for real tissue. These technologies, in combination with human stem cell science, will open new opportuni- ties where renewable sources of cells can be generated to create robust and reproducible 3D models of human tissues for use in drug development. Dr. Kennedy Stem cell–derived organoids are composed of multiple cell types. Although their size and differentiation time can be con- trolled, the exact cellular composition may vary significantly, thus making data interpre- tation difficult and inconsistent. One possi- ble solution is the adoption of "designer ma- trices" to guide the differentiation process. These are synthetic and tunable extracellular matrix proxies that can be designed to more accurately mimic the physical properties and chemical compositions of native extracellu- lar matrices. In turn, designer matrices may lead to more consistent and mature organoid cultures that improve the quality of the data being generated. Roundup Continued from page 14 Drug Discovery Insights Discovery & Development Gene therapy had to regroup after suffering several well- publicized setbacks, but it has been making good progress since 2012, the year the European Union issued its first gene therapy approval for Glybera, a one-time treatment for patients with familial lipoprotein lipase deficiency (LPLD). Although Gylbera has struggled commercially— due to a combination of factors including the drug's ex- pense and LPLD's rarity—the drug has demonstrated that gene therapy can satisfy regulators' safety concerns. According to a recent review in the Journal of Market Access & Health Policy, between 1989 (the year of the first gene therapy) and 2015, 2,335 gene therapy clinical trials were approved worldwide. This review, which was prepared by scientists based at Aix Marseille University, Paris, adds that the number of trials reached its highest peak at the end of the study period, in 2015 (163 trials). Many of the current trials reflect a repair-and-replace strategy—cells are removed, manipulated ex vivo, and returned to the patient. Another approach is to treat the patient directly, which poses special challenges. For ex- ample, the vectors used to insert new genetic material may stimulate an immune response. Also, there is the difficulty of introducing new genes to nondividing cells, such as those in the liver, muscle, and nervous system. Undeterred by these challenges, Pfizer and Sangamo Therapeutics are collaborating on the development and commercialization of direct-in- patient gene therapy programs for hemophilia A. The agreement encompasses SB-525, one of Sangamo's four lead candidates. SB-525 consists of a recombinant adeno-associated virus (rAAV) vector carrying a gene construct for Fac- tor VIII, a blood-clotting protein. The gene construct, a complementary DNA, is driven by a synthetic, liver- specific promoter. The FDA has cleared initiation of clinical trials for SB-525, which also has been granted Orphan Drug designation. According to Sangamo, SB-525 is on track this quarter to start a Phase I/II clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints. These developments parallel the points made in the review article, which noted that regulators "are creat- ing a path for rapid access of new therapies, providing hope for manufacturers, healthcare professionals, and patients." The review, however, adds this caveat: "Payers are increasingly scrutinizing the additional benefits of the new therapies." n A Place for Repair-in-Place Gene Therapy Discovering New Compounds for Drug Development Providing you with techniques and tools necessary to further innovations in early stage screening and drug discovery liebertpub.com/adt Sign Up for TOC Alerts Editor-in-Chief: Andrew D. Napper, PhD

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