Muscle Gene Therapy (eBook)

Preface 6
Contents 9
Contributors 11
1 Animal Models for Inherited Muscle Diseases 15
1.1 Introduction 15
1.2 Dystrophinopathies 16
1.3 Limb-Girdle Muscular Dystrophies 21
1.3.1 Myotilinopathy (LGMD1A) 21
1.3.2 Laminopathy (LGMD1B) 22
1.3.3 Caveolinopathy (LGMD1C) 22
1.3.4 Calpainopathy (LGMD2A) 23
1.3.5 Dysferlinopathy (LGMD2B) 23
1.3.6 Sarcoglycanopathies (LGMD2C–F) 23
1.3.7 TRIM 32 mutations (LGMD2H) 25
1.3.8 Fukutin Related Protein Mutations (LGMD2I) 25
1.4 Laminin a2 (Merosin) deficiency 25
1.5 Centronuclear Myopathies 26
1.6 Other Myopathies 28
1.6.1 Integrin a7 Deficiency 28
1.6.2 Desmin related myopathy 29
1.7 Additional Considerations 29
1.8 Summary and Future Directions 30
References 31
2 In Utero Muscle Gene Transfer 36
2.1 Introduction 36
2.2 Fetal Muscle Development in Relation to In utero Gene Therapy 38
2.3 Candidate Diseases for In utero Muscle Gene Therapy 39
2.4 Vectors for In utero Muscle Gene Therapy 40
2.4.1 Lentiviral Vector 40
2.4.2 Moloney Murine Leukemia Virus-Based Retroviral Vector 41
2.4.3 Adenoviral Vector 42
2.4.4 Adeno-Associated Viral Vector 44
2.4.5 Other Vectors 45
2.5 Summary and Future Directions 45
References 46
3 Gene Therapy for the Respiratory Muscles 54
3.1 Introduction 54
3.2 Respiratory muscle functional assessment: implications for human gene therapy 55
3.3 Challenges for gene transfer to the respiratory muscles: lessons from animal models 57
3.3.1 Direct Intramuscular Diaphragmatic Injection 58
3.3.2 Intracavitary Injection 59
3.3.3 Intravascular Injection 61
3.4 Summary and Future Directions 63
References 63
4 Muscular Dystrophy Gene Therapy in Small Animal Models 67
4.1 Introduction 67
4.2 Gene Therapy for Duchenne Muscular Dystrophy 68
4.2.1 Creation of Minidystrophin Genes 69
4.2.2 Rescue of Muscular Dystrophic Pathology by Delivery of AAV-Minidystrophin 70
4.3 Gene Therapy for Laminin a2-Deficient Congenital Muscular Dystrophy 71
4.4 Gene Therapy for Limb-Girdle Muscular Dystrophies 73
4.5 Summary and Future Direction 77
References 77
5 Antisense-Mediated Exon Skipping for Duchenne Muscular Dystrophy 81
5.1 Introduction 81
5.2 Exon Skipping for Different DMD Mutations 84
5.3 Exon Skipping Applicability 87
5.4 AON Design 89
5.5 From In vitro and In vivo Studies to Patients 91
5.6 Summary and Future Direction 92
References 93
6 Systemic Treatment of Duchenne Muscular Dystrophy by Antisense Oligomer-Induced Exon Skipping 97
6.1 Introduction 97
6.2 Chemistry of Antisense Oligomers 98
6.3 Mechanisms for the Differential Antisense Effect by Systemic Treatment of Unmodified AONs 101
6.4 Exon Skipping and Dystrophin Induction in Cardiac Muscle 103
6.5 Modified PMO for Dystrophin Restoration in Skeletal and Cardiac Muscles 103
6.6 Nonpeptide Polymers for Effective Delivery of PMO 104
6.7 Summary and Future Direction 107
References 107
7 RNAi Therapy for Dominant Muscular Dystrophies and Other Myopathies 110
7.1 Introduction 110
7.2 RNA Interference 111
7.3 RNAi Pathway 111
7.4 RNAi Therapeutics 115
7.5 Disease Allele-Specific Gene Silencing 117
7.6 RNAi Therapy for the Most Common Dominant Muscular Dystrophies 119
7.6.1. Myotonic Dystrophy Type 1 119
7.6.2 Facioscapulohumeral Muscular Dystrophy 120
7.7 Summary and Future Direction 121
References 121
8 Combinatorial Gene Therapy Strategies for Treating Muscular Dystrophies 127
8.1 Introduction 127
8.2 Combining Interventions to Restore Subcellular Structural Organization 128
8.3 Promotion of Muscle Fiber Hypertrophy 132
8.4 Reducing Inflammation and Oxidative Stress in Muscular Dystrophy 134
8.5 Improving Muscles’ Fatigue Resistance 136
8.6 Reducing Muscle Fiber Degeneration and Atrophy 137
8.7 Enhancing Muscle Regeneration 139
8.8 Summary and Future Directions 141
References 142
9 Duchenne Cardiomyopathy Gene Therapy 150
9.1 Duchenne Cardiomyopathy 150
9.2 Dystrophin, Minidystrophin and Microdystrophin 151
9.3 Animal Models for Evaluating Duchenne Cardiomyopathy Gene Therapy 153
9.3.1 Young and Adult Mdx Mice 153
9.3.2 Double Knockout (dko) Models 154
9.3.3 Aged Mdx Model 155
9.3.4 Canine Model for Duchenne Cardiomyopathy 156
9.4 The Therapeutic Threshold for Duchenne Cardiomyopathy Gene Therapy 156
9.5 Treating the Heart Versus Treating Skeletal Muscle 158
9.6 Adeno-associated virus (AAV)-mediated Gene Replacement Therapy for Duchenne Cardiomyopathy 159
9.7 Restore Cardiac Dystrophin Expression with Exon Skipping 162
9.8 Summary and Future Directions 162
References 163
10 Systemic Gene Delivery for Muscle Gene Therapy 172
10.1 Introduction 172
10.2 Advantages and Limitations of Systemic Gene Transfer 173
10.3 Delivery Vehicles 174
10.4 Systemic Delivery of rAAV Vectors in Models of Duchenne Muscular Dystrophy 179
10.5 Limitations of rAAV Vectors for Muscle Gene Therapy 180
10.6 Summary and Future Directions 181
References 182
11 Modulating Immune Responses in Muscle Gene Therapy 189
11.1 Introduction 189
11.1.1 Mechanism of Immune Responses and Tolerance Induction 190
11.1.2 Muscular Dystrophy: Human Disease and Animal Models 193
11.1.3 Preventive Strategies 195
11.1.3.1 Tissue-Specific Promoters 195
11.1.3.2 Alternative Therapeutic Transgenes 196
Utrophin 196
Inhibitor of Myostatin 197
11.1.4 Induction of Central Tolerance 197
11.1.5 Immunosuppression Strategies 198
11.1.5.1 Route of Vector Administration 199
11.1.5.2 Non Viral Vectors 200
11.1.5.3 Adenoviral Vectors 200
11.1.5.4 Retroviral Vectors 201
11.1.5.5 Adeno-Associated Viral (AAV) Vector 202
11.1.6 Systemic Delivery of Therapeutic Genes in DMD Models 205
11.1.7 Immune Responses Related to the AAV Capsid 205
11.2 Summary and Future Directions 206
11.3 Future Directions 207
References 207
12 Delivering Large Therapeutic Genes for Muscle Gene Therapy 213
12.1 Introduction 213
12.2 AAV Vector 214
12.2.1 Overview 214
12.2.2 Single Vector Approach Based on VP2-Null AAV Viruses 215
12.2.3 Single Vector Approach Based on AAV Serotype 5 216
12.2.4 Dual Vector Approach via Cis-activation 217
12.2.5 Dual Vector Approach via Trans-Splicing 217
12.2.6 Dual Vector Approach via Overlapping 218
12.2.7 Hybrid Dual Vector Approach 219
12.3 Adenoviral Vector 219
12.4 Herpes Simplex Viral Vector 221
12.5 Summary and Future Directions 222
References 222
13 Muscle as a Metabolic Factory for Gene Therapy 227
13.1 Introduction 227
13.2 McArdle Disease 228
13.3 Pompe Disease 230
13.4 Clinical Trials Targeting Muscle as a Metabolic Factory 233
13.5 Summary and Future Directions 235
References 235
14 Muscle as a Target for Genetic Vaccine 239
14.1 Introduction 239
14.2 Muscle as the Target for Vaccine 240
14.3 DNA Vaccine 241
14.4 Viral Vectors for Vaccine Development 243
14.4.1 Adenoviral Vector for Vaccine Development 243
14.4.2 Adeno-associated Viral Vector for Vaccine Development 246
14.5 Challenges and Future Directions in Genetic Vaccine Development: A Case Study of the Genetic Vaccine for HIV 249
14.8 Conclusion 250
References 250
15 Combining Stem Cells and Exon Skipping Strategy to Treat Muscular Dystrophy 256
15.1 Introduction 256
15.2 AON-Mediated Exon Skipping to Treat DMD 258
15.3 Cell-Based DMD Therapy with Muscle Derived CD133+ Stem Cells 259
15.4 Combining Exon-Skipping Therapy and CD133+ Cell Therapy to Treat DMD 260
15.5 Summary and Future Directions 260
References 261
16 Gene Therapy Clinical Trials for Muscular Dystrophies 264
16.1 Introduction 264
16.2 Regulatory Issues for Gene Therapy Trials in Muscular Dystrophy 265
16.3 The Step from Pre-clinical Experimental Studies to Clinical Trials 266
16.4 Methods of Monitoring Effects of Treatment 266
16.5 Outcome Measures 267
16.6 Past and Current Clinical Trials 267
16.6.1 Plasmid Gene Transfer 267
16.6.2 AAV Based Gene Transfer 268
16.6.3 Cell Based Gene Transfer 269
16.6.4 Antisense Mediated Exon-skipping 270
16.7 Summary and Future Directions 271
References 271
Index 275