2016 Archived Content

CRISPR and RNAi for Drug Discovery Track Banner

Cambridge Healthtech Institute’s inaugural conference on Use of CRISPR & RNAi for Drug Discovery will cover the latest in the use of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9-based gene editing and RNA interference (RNAi) for use in drug discovery and for developing novel drug therapies. It will bring together experts from all aspects of basic science and clinical research to talk about how and where gene editing and RNAi can be best applied. The talks will discuss how the CRISPR/Cas system compares to RNAi and if they can be used in a complementary fashion. Scientists and clinicians will share best practices on everything from assay design to data analysis when conducting low and high throughput screens and generating cellular models, both in vitro and in vivo, using CRISPR/Cas9, siRNA (small interfering RNA), and shRNA (short hairpin RNA) for functional screening, pathway analysis, target discovery, disease modeling, and for enabling cell and viral therapies.

Suggested Event Package:

14 - 15 November: Preclinical Models for Cancer Immunotherapy and Combinations

15 - 16 November: Use of CRISPR & RNAi For Drug Discovery

15 November Dinner Short Course*: (SC3) Functional Screening Strategies Using CRISPR and RNAi

*Separate registration required.

Tuesday 15 November

12:00 Registration


13:30 Chairperson’s Opening Remarks

Lorenz Mayr, Ph.D., Vice President and Global Head, Biological Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D

13:35 Applications of CRISPR/Cas9 for Drug Discovery

Lorenz_MayrLorenz Mayr, Ph.D., Vice President and Global Head, Biological Reagents & Assay Development, Discovery Sciences, AstraZeneca R&D

This presentation will describe the use of CRISPR/Cas9 technology for target-validation studies in our in vitro and in vivo disease models at AstraZeneca. I will describe our activities with in-house programs and strategic external partnerships towards genome-wide target discovery and target validation studies. I will discuss in detail our unique approach towards innovation & collaboration, case studies from our drug discovery programmes and future outlook of gene editing for drug discovery & therapeutic applications.

14:05 Generation of in vivo Preclinical Models with the CRISPR/Cas9 System

Danilo_MaddaloDanilo Maddalo, Ph.D., Lab Head, ONC Pharmacology, Novartis Institutes for BioMedical Research, Novartis Pharma AG

Animal models faithfully recapitulating genetic lesions driving tumour formation/progression are key to fully understand cancer origin and progression. In vivo genome editing of somatic cells offers the unprecedented possibility of modeling such lesions by delivering the CRISPR/Cas9 system to specific tissues. In this talk we will discuss the state-of-the-art of preclinical models before and after the CRISPR revolution.

14:35 Large Scale CRISPR Screens for Discovery of Genotype Specific Combination Therapies

Roderick_BeijersbergenRoderick Beijersbergen, Ph.D., Group Leader, Netherlands Cancer Institute and Head, NKI Robotics and Screening Center

The success of targeted therapeutics in cancer therapy is limited with respect to long-term survival and can potentially be improved with combination therapies. We apply large-scale CRISPR screens for the identification of dependencies in the context of specific genetic alterations in combination with targeted drugs. We have identified novel effective drug combinations and the results of this work and the clinical implications will be discussed.

15:05 Refreshment Break in the Exhibit Hall with Poster Viewing

15:45 Identifying Targets for Cancer Therapeutics Using High Throughput Screens and Clinically Relevant 3D Cell Culture Models

Geoffrey_BartholomeuszGeoffrey Bartholomeusz, Ph.D., Associate Professor and Director, Target Identification and Validation Program, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

The use of two-dimensional monolayer cell cultures platforms that inadequately represent the complex tumor microenvironment has contributed to the dismal rate of discovery of new and effective anticancer therapies despite a significant financial investment. Our studies have been focused on developing clinically relevant three-dimensional cell culture systems that are utilized for high throughput RNAi screens to identify new targets for novel anti-cancer drug development.

16:15 Combinatorial Interpretomics: Drawing on the Power of Combinatorial Genomic/Imaging Datasets in the Interpretation of Large Scale Screens

Arvind_RaoArvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center

In this talk, we will draw on studies from drug screening and RNAi to describe data mining workflows to go from phenotypic measurements to biological insight. Modern bioinformatics tools and multiple public databases (like CCLE, LINCS) allow interesting investigations in multimodal data integration. Our goal is to present a view of what’s possible, using case studies from RNAi screening in triple negative breast cancer, and drug screening in glioblastoma.

16:45 Functional Genome-Wide Genetic Analysis Using Optimized CRISPR Pooled Screens and Driver-Map Gene Expression Profiling

Paul_DiehlPaul Diehl, Ph.D., COO, Cellecta, Inc.

Well-designed pooled lentiviral-based genome-wide and targeted CRISPR/RNAi libraries provide one of the most effective tools for identifying genes functionally required for biological responses. Combining these screens with gene expression data of the target model systems produces a comprehensive picture of the genetic drivers related to a phenotype. We will review developments and improvements that enhance the consistency, robustness, and efficacy of both CRISPR/RNAi screens and gene expression profiling for therapeutic target discovery and marker identification. 

17:15 Interactive Breakout Discussion Groups

Topic: Combinatorial Interpretomics (Integrating Imaging, Genomics, Functional Genomics) For Hypothesis Generation and Drug Discovery

Moderator: Arvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center

  • Opportunities for phenotype guided informatics in large scale (CRISPR/RNAi/drug) screens
  • How can we leverage large scale efforts like TCGA, ICGC for "rational" hit finding
  • What would a multimodal decision engine (across imaging, genomics, drug databases (like CCLE, LINCS, CMap) look like? What capabilities are we looking for, what would be "nice to have"?

    Topic: Going all the way?: Genome-wide Screens or Focused Collections

    Moderator: Roderick Beijersbergen, Ph.D., Group Leader, Netherlands Cancer Institute and Head, NKI Robotics and Screening Center

    • What are the practical consequences of screens at a genome-wide scale?
    • Strategies to pre-select focused gene sets for smaller, more effective screens

    18:15 Close of Day

    18:3021:00 Recommended Dinner Short Course*

    (SC3) Functional Screening Strategies Using CRISPR and RNAi

    * Separate registration required

    Wednesday 16 November

    8:00 Registration


    8:25 Chairperson’s Remarks

    Ralph Garippa, Ph.D., Director, RNAi & Gene Editing Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center

    8:30 Novel Immune Checkpoints Identified by RNAi Screening

    Tillman_MichelsTillmann Michels, Head of Research Group, Immune Checkpoint Inhibitors, Department of Interventional Immunology, Regensburg Center for Interventional Immunology; Member, Department of Translational Immunology, German Cancer Research Center

    A highlight in cancer therapy is immune checkpoint blockade. With a siRNA high throughput screening we identified novel immune modulators in various cancer entities. Even though immune checkpoints are entity specific, the underlying mechanisms of immune modulation are shared among them. Abrogation of TIL-mediated apoptosis and cAMP-mediated inhibition of TILs are some of the utilized modes of action.

    9:00 A Loss of Function RNAi Screen to Identify New Pathways and Genes Essential for Nucleolar Stress Response

    Kaylene_SimpsonsKaylene J. Simpson, Ph.D., Associate Professor and Head, Victorian Centre for Functional Genomics ACRF Translational RPPA platform, Peter MacCallum Cancer Centre, Australia

    We have used high content imaging to perform genome-wide high content loss-of-function (RNAi) and gain of function (ORF overexpression) screens, and screened compound libraries of clinically approved therapeutics, to unbiasedly identify the critical genes and pathways implicated in the nucleolar stress response due to ribosomal protein haploinsufficiency. We are currently validating these results using in vitro and in vivo models.

    9:30 Vertical Integration of CRISPR/Cas9 Genome Engineering in Drug Discovery

    Fischer_DavidDavid F. Fischer, Ph.D., Executive Director Biology and DMPK, Charles River Discovery

    Genome engineering technology (CRISPR/Cas9) can be utilized in every aspect of the drug discovery process. This includes in vitro models for high-throughput screening (HTS) such as various cell lines and hESC or iPSC, mouse models by editing mESC, as well as syngeneic models matching human tumors. In addition, the technology is important for in vitro screening, by creation of large arrays of gRNAs, similar to the Charles River SilenceSelect RNAi technology. Case study examples will be explored.

    10:00 Evaluation of a Novel siRNA Technology to Reduce Off-Target Effects Using High Content Analysis

    Marc_BickleMarc Bickle, Ph.D., Head Technology Development Studio, Max Planck Society of Molecular Cell Biology and Genetics

    RNA interference suffers from the phenomenon of off-target effects leading to genes other than the intended target being downregulated. Many methods have been devised to address the problem. We investigate the off-target effect of siPOOLs, which target each gene with a pool of 30 selected siRNAs. We measure off-target effects by automated microscopy quantifying many parameters and comparing the resulting profiles.

    10:30 Coffee Break in the Exhibit Hall with Poster Viewing

    11:15 Systematic Comparison of CRISPR/Cas9 and shRNA Screens for the Identification of Drug Targets and Essential Genes

    Michael_BassikMichael Bassik, Ph.D., Assistant Professor, Department of Genetics, Stanford University

    We compare the ability of shRNA and CRISPR/Cas9 screens to identify essential genes and drug targets. We find the precision of the two libraries is similar, but that results from the two screens are markedly different. This can be partially explained by identification of distinct biological processes with each technology. Combining data from both screens improves performance and gives a more complete biological picture.

    11:45 Pooled CRISPR-Cas9 Screening: A Powerful Functional Genomics Tool for Translating Biological Entities into Druggable Targets

    Ralph_GarippaRalph Garippa, Ph.D., Director, RNAi & Gene Editing Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center

    CRISPR represents a robust way to conduct genetic screens, combining the ease of directing Cas9 endonuclease via sgRNA, with multiple target site availability per gene. The technique has largely been built upon advancements made in RNAi, in a pooled or arrayed manner. We highlight specific examples, attesting to the power of functional genomics in advancing our understanding of cancer regulatory networks.

    12:15 Technology Panel: Trends in CRISPR & RNAi Technologies

    This panel will bring together 2-3 technical experts from leading technology and service companies to discuss trends and improvements in library design, assay reagents and platforms, and data analysis tools that users can expect to see in the near future.

    Moderator: Ralph Garippa, Ph.D., Director, RNAi & Gene Editing Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center

    Panelists: Paul Diehl, Ph.D., Director, Business Development, Cellecta, Inc.

    David F. Fischer, Ph.D., Executive Director Biology and DMPK, Charles River Discovery

    Kristofer J. Müssar, Ph.D., MBA, MS, Managing Director,  Europe, Cyagen Biosciences GmbH 

    12:45 Enjoy Lunch on Your Own


    14:15 Chairperson’s Remarks


    14:20 iPSCs and Genome Engineering: A Perfect Match for Drug Discovery

    Nazish Sayed, M.D., Ph.D., Instructor, Cardiovascular Institute, Stanford University


    14:50 Chemogenomics Using CRISPR - Old Tricks for New Dogs

    Dominic_HoepfnerDominic Hoepfner, Ph.D., Researcher, Developmental & Molecular Pathways, Novartis Institutes for BioMedical Research, Novartis Pharma AG

    Phenotypic screens identify compounds with interesting biological responses, however lack of mechanism of action knowledge can hamper further therapeutic development. Chemogenomic profiling has a proven track record in target identification of bioactive compounds, but its dependence on genome-wide deletion collections limited its application to lower eukaryotic systems. Here we provide examples how the CRISPR/Cas9 system allows adaptation of yeast HIP-HOP profiling to mammalian cells. 

    15:20 MicroRNA Target Site Editing by CRISPR-Cas9 in Primary Human Chondrocytes

    Christine_SeidlChristine Seidl, Ph.D., Post-Doctoral Research Associate, Cell Signaling, Kennedy Institute of Rheumatology, Oxford University

    Therapeutic approaches in the context of microRNAs (miR) have been limited due to the fact that one miR frequently targets multiple mRNAs. This would lead to unwanted and possibly severe side effects if total miR levels were to be altered. In this proposal, a method will be described that employs CRISPR-Cas9 for editing specific miR-target sites on an mRNA rather than miR levels in primary human chondrocytes thus enabling once more an approach for miR-based therapeutics.

    15:50 Close of Conference