CRISPR Therapeutics AG · NASDAQ:CRSP
CRISPR Therapeutics — GTC Bio Cell and Gene Therapy (September 2015)
20 slides from CRISPR Therapeutics's conference presentation, Sep 9, 2015
Slide 1: Gene Editing with CRISPR/Cas9: Opportunities for Human Therapeutics
GENE EDITING WITH CRISPR/CAS9: OPPORTUNITIES FOR HUMAN THERAPEUTICS Bill DATELundberg, MD CSO, CRISPR Therapeutics September 9, 2015
Slide 2: Disclosures
Disclosures § I am a paid employee of and own shares in CRISPR Therapeu8cs § The opinions expressed here are my own 2
Slide 3: The CRISPR Craze
The CRISPR Craze “Now you can essentially change a genome at will to almost anything you want. The sky's the limit.” - Craig Mello Nobel Laureate 2006 and Scientific Founder CRISPR Therapeutics # publications 3
Slide 4: The CRISPR-Cas Adaptive Immune System
The CRISPR-Cas Adaptive Immune System 4 Baya et al. Ann. Rev. Genet. 2011
Slide 5: CRISPR-Cas9 as a Tool for Gene Editing
CRISPR-Cas9 as a Tool for Gene Editing Cas9 programmed with crRNA:tracrRNA duplex or single guide RNA (sgRNA) “…RNA programmed Cas9 … could offer considerable potential for gene-targeting and genome-editing applications” Jinek Chylinski… Doudna Charpentier Science (2012) Cas9 “Nickase” and dCas9 Cas
Slide 6: CRISPRs vs. TALENs in hPSCs
CRISPRs vs. TALENs in hPSCs g Efficiency of CRISPRs Versus TALENs in Human Pluripotent Stem Cells Table S1. Targeting Efficiency of CRISPRs Versus TALENs in Human Pluripotent Stem Cells osome: TALENs Chromosome: CRISPRs TALENs ition a Cell Position a Cell Target Sequence Gene Efficiency Efficiency E
Slide 7: CRISPR/Cas vs. TALEN
CRISPR/Cas TALEN VS. Efficiency 50-80% 0-30% (% of mutant clones) 7-25% Homozygous KOs 0% >10% Knock-ins ~1% Ding et al. Cell Stem Cell 2013
Slide 8: Low Incidence of Off-Target Mutations
Low Incidence of Off-Target Mutations Off-Target Sites N-Fold Enrichment of Reads with Variants (vs. Control) crCCR5 Significant Off-Target On-Target Total Sites Off-Target InDel Off-Target Other Sites* Combined Combined** A 19 0 0.83 1.16 1.06 39.87 B 30 1* 1.14* 1.28 1.22 63 C 23 0 1.07 0.94 0.96
Slide 9: Off Target Frequency Compared to Control
Off Target Frequency - Compared to Control 100 64.433 91.176 Mock 10 CRISPR Indel Frequency % 1 0.1 0.01 0.001 9 CRISPR Internal Data
Slide 10: Cool Things You Can Do With CRISPR
Cool Things You Can Do With CRISPR Genetic Screens Shalem et al. Shalem et al. Science 2014 Page 8 Author Manuscript Gene Editing Wang et al. Page 14 Animal Models Wang et al. Page 14 Author Manuscript Fig. 2. GeCKO library design and application for genome-scale negative selection screening NIH-PA
Slide 11: Cool Things You Can Do With CRISPR
7/29/2015 Dr. Someone (@Splinky2112) | Twitter Cool Things You Can Do With CRISPR “It Just Works” New to Twitter? Sign up Publications • Gene disrupt or correct Search Twitter #CRISPRFacts Have an account? Log in • Genome-scale screens TWEETS FOLLOWING FOLLOWERS FAVORITES Follow 94 81 18 170 • Modif
Slide 12: Gene Editing - Principles
Gene Editing - Principles • Guide design matters - Highly selective guides can be identified • Cell type matters – Editing efficiency varies across different cell lines/cell types • Cannot predict relative ability to delete intervening DNA between to guide sites from individual guide NHEJ disruption
Slide 13: Delivery - Key Challenge For In Vivo Applications
Delivery - Key Challenge For In Vivo Applications Ex vivo In vivo HSCs Liver • Monogenic diseases • Metabolic diseases • Enzyme replacement • Enzyme replacement • Other indications e.g. HIV Delivery Eye Oncology cell Required • Monogenic diseases therapies • Complex indications • CAR-Ts, TCR Other o
Slide 14: Making a CRISPR Medicine: Some of the Challenges
Making a “CRISPR” Medicine: Some of the Challenges • Pharmacodynamics • Regulatory framework and Product Development: Selecting the Dose as an example • Safety – off-target effects • Manufacturing and controls 14
Slide 15: Pharmacodynamics (Proof-of-Principle)
Pharmacodynamics (Proof-of-Principle) • Animal Models – Do they need to be “Humanized” ? • Assess Pharmacology: • “Amount” of gene edit • Functional tests (restoration of function) • Marker of biological activity • Impact on ‘clinical’ endpoint • Comparability to product candidate 15
Slide 16: Regulatory Framework and Product Development: Selecting the Dose
Regulatory Framework and Product Development: Selecting the Dose as an Example 13 April 2012 EMA/CAT/GTWP/671639/2008 Committee for Advanced Therapies (CAT) Considerations for the Design of 1 23 March 2015 2 Early-Phase Clinical Trials of 1 3 Guideline on quality, EMA/CAT/80183/2014 Committee for Ad
Slide 17: Manufacturing Process and Quality
Manufacturing Process and Quality Ex-vivo CD34+ HSC as an Example 17
Slide 18: Creating CRISPR-Based Therapeutics
Creating CRISPR-Based Therapeutics • CRISPR-based gene editing is efficient and can be highly specific • Optimizing guides is largely empiric and system dependent • Creating a new medicine requires good drug development • CRISPR Therapeutics research operations established in Cambridge MA – expandin
Slide 19: CRISPR-Cas9 Mediated Genome Engineering
CRISPR-Cas9 Mediated Genome Engineering 19 Doudna and Charpentier Science 2014
Slide 20: Gene Editing with CRISPR/Cas9: Opportunities for Human Therapeutics
GENE EDITING WITH CRISPR/CAS9: OPPORTUNITIES FOR HUMAN THERAPEUTICS Bill DATELundberg, MD CSO, CRISPR Therapeutics
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