1 Table of Contents 1 Table of Contents 5 1.1 List of Tables 7 1.2 List of Figures 8 2 Introduction 10 2.1 Gene Therapy - Definitions 10 2.2 Report Coverage - the Emerging Gene Therapy Pipeline 11 2.3 History of Gene Therapy 12 2.4 Limitations of Gene Transfer 13 2.5 The Development of Targeted Gene Editing 13 2.6 Overview of Gene Editing Platforms 13 2.6.1 Zinc Fingers (1996) 13 2.6.2 Transcription Activator-Like Effectors (2011) 14 2.6.3 The CRISPR/Cas System (2013) 15 2.6.4 Effectors for Targeting Domains 19 2.6.5 Comparison of Gene Editing Systems 19 2.6.6 Summary of Gene Editing Systems 19 2.7 Overview of In Vivo Gene Therapy 21 2.7.1 Editing is Dependent on Cell Type, Stage, and Repair Pathway 21 2.7.2 Delivery 21 2.7.3 Emerging Safety Concerns with Editing Platforms 24 2.7.4 Editing Products are Reliant on the Target Cell’s Cycle Stage and DNA Repair Machinery 27 2.7.5 Advantages of Gene Editing over Gene Transfer 28 2.7.6 Integration into ‘Safe Harbor’ Sites 28 2.7.7 The Increasing Complexity of Gene Therapy 30 2.7.8 Summary of In Vivo Gene Therapy 31 3 Gene Therapy - Near Term Product Pipeline 33 3.1 Leber Congenital Amaurosis 33 3.1.1 Unmet Need 33 3.1.2 Molecular Genetics 33 3.1.3 Luxturna (Voretigene neparvovec) 33 3.1.4 Editas Medicine: EDIT-101 35 3.1.5 Trial Design 36 3.1.6 EDIT-101 and Off-Target Effects 37 3.1.7 The Potential Advantage of EDIT-101 is the Longevity of its Therapeutic Effect 37 3.1.8 Summary - LCA 38 3.2 Choroideremia 38 3.3 Hurler Syndrome (MPS I) 39 3.3.1 Key Clinical Studies 40 3.3.2 Regenex: RGX-111 40 3.3.3 Sangamo Therapeutics: SB-318 40 3.4 Hunter Syndrome (MPS II) 41 3.4.1 Unmet Need 41 3.4.2 Sangamo Therapeutics: SB-913 41 3.4.3 Immusoft Corporation: Cell Therapy 43 3.5 Sanfilippo Syndrome (MPS III) 43 3.5.1 Lysogene: LYS-SAF302 43 3.6 Summary - MPS Disorders 44 3.7 Hemophilia 44 3.7.1 Hemophilia A 46 3.7.2 Summary - Hemophilia A 50 3.7.3 Hemophilia B 51 3.7.4 Summary - Hemophilia B 53 3.8 Hemoglobinopathies 54 3.8.1 Beta Thalassemia: Unmet Need 54 3.8.2 Beta Thalassemia: Molecular Genetics 55 3.8.3 Sickle Cell Disease: Unmet Need 56 3.8.4 Sickle Cell Disease: Molecular Genetics 56 3.9 Cellular Therapies for Hemoglobinopathies 57 3.9.1 Blue Bird Bio: BB-305 (‘LentiGlobin’) 57 3.9.2 Sangamo: ST-400 60 3.9.3 CRISPR Therapeutics: CTX-001 61 3.9.4 Summary: Cellular Therapies for Hemoglobinopathies 62 3.10 Duchenne Muscular Dystrophy 63 3.10.1 Unmet Need 63 3.10.2 Molecular Genetics 63 3.10.3 ExonDys 51 - Sarepta Therapeutics 64 3.10.4 Solid BioSciences: SGT-001 66 3.10.5 Exonics Therapeutics: CRISPR Approach 67 3.10.6 Summary - Duchenne Muscular Dystrophy 68 4 Competitive Landscape 69 4.1 Regulatory Considerations for Developing Gene Therapy Products 69 4.1.1 Product Characteristics 69 4.1.2 Clinical Study Design for Gene Therapy Products 69 4.1.3 Disease specific guidance 70 4.1.4 Reimbursement and Payment 71 4.1.5 Summary - Regulatory Considerations 72 4.2 Intellectual Property - CRISPR/Cas 72 4.2.1 Licensing, Exploitation, and MPEG Pool 74 4.3 Company Analysis: Gene Editing Companies 75 4.3.1 Sangamo Therapeutics 75 4.3.2 CRISPR Therapeutics 79 4.3.3 Casebia Therapeutics 81 4.3.4 Editas Medicine 82 4.3.5 Intellia Therapeutics 84 4.3.6 Homology Medicines 86 4.4 Company Analysis: Pharma 87 4.4.1 Amgen 87 4.4.2 Gilead Sciences 87 4.4.3 Novartis 87 4.4.4 Sanofi 88 4.4.5 GlaxoSmithKline 88 4.4.6 Pfizer 88 5 Appendix 89 5.1 References 89 5.2 Report Methodology 98 5.3 About GBI Research 99 5.4 Disclaimer 99

1.1 List of Tables Table 1: Pipeline Products Covered 13 Table 2: Properties of Standard Gene-Editing Nucleases 20 Table 3: Registered Clinical Trials of CAR-T Cell Therapies Using Gene-Editing 21 Table 4: Gene Therapy Clinical Trials Worldwide by Vector 24 Table 5: Gene Editing Landscape, Vector Differentiation by Target Tissue 25 Table 6: Gene Editing Landscape, Key Off-Target Effect Studies 26 Table 7: Pre-existing Immunity to Cas9 27 Table 8: Characterization of the Rate of Homology Directed Repair in Range of Cell Lines 28 Table 9: Comparison of Gene Editing and Gene Transfer Approaches 29 Table 10: Gene Editing Landscape, Pipeline of Targeted Gene Editing Products by Company 32 Table 11: Luxturna Clinical Studies 35 Table 12: EDIT-101 - Phase I/II Trial Design and Comparison to Luxturna Efficacy Study 38 Table 13: Dose Response in CEP290 Gene Editing and CRISPR Expression 39 Table 14: Gene editing landscape, Mucopolysaccharidosis I (MPS I) (Hurler Syndrome), Diagnosed, Prevalent Cases, 2017-2027 40 Table 15: Key Phase I/II Studies in MPS I 41 Table 16: Gene editing landscape, Mucopolysaccharidosis II (MPS II) (Hunter Syndrome), Diagnosed, Prevalent Cases, 2017-2027. 42 Table 17: SB-913 Trial Design 43 Table 18: SB-913 - Interim Results 43 Table 19: LYS-SAF302 Phase II/III Trial Design 44 Table 20: Gene Editing Landscape, MPS Disorders 45 Table 21: Gene Editing Landscape, Hemophilia Epidemiology and Forecast, 2016-2026. 46 Table 22: Scale of Hemophilia Severity 47 Table 23: Phase I/II Hemophilia A Trials 48 Table 24: BMN-270 Factor VIII Levels at 1.5 Years (High Dose) 49 Table 25: Gene Therapy Landscape, Phase I/II Clinical Trial Design for Hemophilia A 50 Table 26: Gene Therapy Landscape, Summary of Key Pipeline Gene Therapies for Hemophilia A 51 Table 27: Phase I/II Clinical Studies 52 Table 28: Gene Therapy Landscape, Overview Of Key Pipeline Products in Hemophilia B 54 Table 29: Gene editing landscape, Thalassemia, Diagnosed, Prevalent Cases, 2017-2027 55 Table 30: Frequent Mutations Causing SCD 57 Table 31: Phase I/II Clinical Studies 58 Table 32: LentiGlobin - Ongoing Phase III Trials in Beta Thalassemia 59 Table 33: Results of LentiGlobin trials in Thalassemia and Sickle Cell Disease 60 Table 34: ST-400 Trial Design Compared with LentiGlobin 62 Table 35: CTX-001 trial design (Left) against ST-400 and LentiGlobin (Right) 63 Table 36: LentiGlobin (BB-305) may Achieve Blockbuster Status by 2023 64 Table 37: Gene Therapy Landscape, DMD, Global Prevalence (%) 64 Table 38: Exondys 51 - Clinical Studies 66 Table 39: SGT- 001 Study Design 67 Table 40: Gene Therapy Landscape, Key Patents in the CRISPR Dispute 74 Table 41: Gene Therapy Landscape, IP Estates of CRISPR Companies 75 Table 42: Gene Therapy Landscape, ERS Genomics EU Licensing 2004-2018 76 Table 43: Sangamo Therapeutics Pipeline, September 2018 76 Table 44: Sangamo Therapeutics Partnerships 78 Table 45: Sangamo Therapeutics SWOT 79 Table 46: CRISPR Therapeutics Pipeline 80 Table 47: CRISPR Therapeutics Pipeline 81 Table 48: CRISPR Therapeutics SWOT 82 Table 49: Casebia Pipeline, September 2018 82 Table 50: Editas Medicine Pipeline, September 2018 83 Table 51: Editas Medicine Pipeline, September 2018. 84 Table 52: Editas Medicine SWOT 85 Table 53: Intellia Therapeutics Pipeline 85 Table 54: Intellia Therapeutics SWOT 86 Table 55: Homology Medicines Pipeline 87 Table 56: Homology Medicines SWOT 881.2 List of Figures Figure 1: Nucleases Based on Protein-DNA Interactions 14 Figure 2: Transcription Activator-Like Effector Nucleases (TALENs) 15 Figure 3: The CRISPR/Cas System 16 Figure 4: CRISPR/Cas Binding Mechanism 17 Figure 5: Cas9 Orthologs 18 Figure 6: Gene Therapy Clinical Trials Worldwide by Vector 22 Figure 7: Multiple Sangamo Therapeutics Products Use an Albumin Targeting ‘Safe Harbor’ Approach 29 Figure 8: Gene Editing Landscape, Progression of Gene Therapy Applications 30 Figure 9: Gene Editing Landscape, Hemophilia A + B 44 Figure 10: SPK-9001: Factor IX Activity after SPK-9011 in 8 Participants that did not Show AAV Capsid-Directed Immune Response 53 Figure 11: Cost of Beta-Thalassemia Major Treatment as of NHS Tariffs at 2013/14 Prices 55 Figure 12: BCL11A is Involved in Fetal Hemoglobin Silencing 60