OCT 03, 2018 12:00 PM PDT

Using CRISPR and Stem Cells to Treat Genetic Disease

Presented at: CRISPR 2018
Speaker
  • Senior Investigator, Gladstone Institute of Cardiovascular Disease, Professor Department of Medicine, Division of Genomic Medicine, University of California, San Francisco
    Biography
      Bruce R. Conklin is an Investigator at the Gladstone Institutes and a Professor at UCSF in the departments of Medicine, Ophthalmology and Pharmacology. Conklin is also the Deputy Director of the Innovative Genomics Institute. His research focuses on biomedical applications of CRISPR technology with an emphasis on allele-specific editing of dominant negative disease genes in the retina, motor neurons and cardiac tissue. Conklin uses patient-specific iPSC-derived tissues for pre-clinical genome surgery studies. Conklin began research training with Julius Axelrod, Ph.D., (Nobel Laureate, NIH), did his residency at Johns Hopkins and a postdoctoral fellowship with Henry Bourne (UCSF). In 1995 Conklin joined the Gladstone Institutes and UCSF as faculty. Conklin is the founder of several public stem cell and genomics projects including BayGenomics, GenMAPP and WikiPathways. He pioneered the use of designer G protein coupled receptors (RASSLs) for tissue engineering. He is the Gladstone Scientific Officer for Technology & Innovation. He serves on multiple scientific advisory boards including the Allen Institute for Cell Science, Chinese University of Hong Kong, Tenaya Therapeutics and the Exploratorium. He is a member of the American Society for Clinical Investigation, and is a Fellow in the California Academy of Sciences.

    Abstract

    Decoding human genetic disease allows us to develop models of the pathology that can be directly tested with gene correction or targeted drug therapy.  Dominant negative mutations are particularly promising therapeutic targets since they are resistant to traditional therapies, yet precise excision of disease-causing allele could provide a cure. We are using patient-derived induced pluripotent stem cells (iPSCs) to model diseases in tissues that are particularly susceptible to dominant negative mutations: cardiomyocytes, motor neurons and retinal pigment epithelial (RPE) cells. By developing CRISPR genome surgery in human cells, we hope to devise improved cellular models as well as human therapies.  By focusing on allele-specific gene excision we can select gene mutations that are highly penetrant, with clear phenotypes in cell types that can be readily derived from iPSCs.  We use whole genome sequencing to identify common genetic polymorphisms that can be used to selectively inactivate the disease allele with CRISPR nucleases.  The diseased cell types allow us to decode the cellular signatures of disease and determine if the excision of the disease allele restores cellular functioning.  Genome surgery is a rapidly advancing field that uses state-of-the-art techniques that pushes the boundaries of cell and molecular biology. We use advanced microscopy, tissue engineering and single cell genomics to optimize precise editing. We are developing computational methods to select optimal CRISPR/Cas9 combinations in diverse populations. We aim to produce therapies that are safe and cost effective so that they can benefit the maximal number of people. In collaboration with clinical scientists and the Innovative Genomics Institute (https://innovativegenomics.org/) we are preparing large animal models and clinical grade reagents to prepare for human clinical trials.  

    Learning Objectives: 

    1. Specific examples of where genome surgery could be used
    2. Future directions in genome surgery


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