Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com September/October 2018 Clinical OMICs 15 to any researcher, whether working in the commercial set- ting or academia. The even bigger challenge than the sample collection is building an open-source platform of all of the biological and clinical data and making it available through a portal that anyone can use. To help overcome this, Answer ALS has given GNS Healthcare access to their data. Funded by the ALS Association, GNS will use its machine learning plat- form, REFS, to help create a comprehensive disease model. GNS states that they will "transform these petabytes of patient data into mechanistic models, connecting genetic, molecular, and biochemical variables to clinical outcomes that will allow in silico experiments to be performed at a rapid rate on the computer." Another focus of this omics-based work is to create sub- types of ALS patients, in order to personalize treatment and stratify clinical trials. This is one of the main goals of the Genomic Translation for ALS Clinical Care (GTAC) pro- gram, a collaboration between Biogen, the ALS Association, and Columbia University Medical Center (CUMC) launched three years ago. GTAC is heavily focused on classifying ALS patients into subgroups based on similar RNA transcriptomic profiles. Once these data are made available, clinicians could offer more personalized and effective treatment after a simple blood test on a patient. In addition to new gene discovery and genotype–phenotype correlations, GTAC is also taking careful exposure and epidemiological data on their patients, noting e n v i ro n m e n t a l f a c t o r s that have been rumored to play a role in ALS like chemical exposure, jobs, and living areas. While it might seem this work would have been done long ago as a build- ing block to better under- stand the disease, Matthew Harms, M.D., the director of GTAC and an associate profes- sor of neurology at the Columbia University College of Phy- sicians and Surgeons, told Clinical OMICs that, "we have always known that there are biologically relevant clusters of ALS patients that we haven't had the tools to detect." He credits new technology and the falling cost of sequencing as opening "a whole new wave of study." It is this new set of tools enabling renewed study of ALS that has Rosenstein energized and optimistic. Looking ahead to 2030, he said assuredly that "we'll have drugs," to treat the disease. Lee added that it may not be so easy. One hurdle, he said, is that CRISPR strategies targeting CAG repeats may "suffer from signifi- cant off-targeting because there are many genes containing CAG repeats in the genome." Because of this, researchers need to "capi- talize on other genetic variations that selectively generate CRISPR [protospacer adjacent motif ] sites [sequences required for Cas9 function] on the mutant HTT gene for allele-specific targeting." "Many independent CAG expansion mutations might have happened over time, generating mutant HTT gene on diverse haplotype backbones," Lee said. "Therefore, mutant-specific CRISPR strategies have to be designed after considering both mutant and normal haplotypes in a given patient, requiring fully customized approaches." Dunbar said there is also another hurdle. The biggest obsta- cle will be to "deliver the CRISPR-Cas9 effectively to cells that need it most. We are working on packaging the system in an AAV9 virus or by using nanoparticle (dendrimers) that cross the blood-brain-barrier as a potential means of delivery." Lee agreed that the "development of delivery methods and CRISPR systems that are efficient, specific, and safe [will] likely make CRISPR HD intervention trials possible." As to when this may become a reality, Lee said "It is hard to pre- dict when, but technology development can be much faster than we anticipate." Dunbar added another layer of optimism, noting that the technology may be even wider reaching than just HD. When asked if this technology could be ap- plied to other neurodegen- erative disorders, Dunbar is hopeful and said that he thinks "a tool like CRISPR will be adopt- ed for polygenetic dis- orders, as CRISPR can be adapted to hit mul- tiple targets." —Julianna LeMieux, Ph.D. n Matthew Harms, M.D., director, GTAC Huntington's disease affects the basal ganglia region of the brain. TIM VERNON / SCIENCE PHOTO LIBRARY / Getty Images

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