Details

Autor(en) / Beteiligte

• Lu, Yanmei
• Gorovits, Boris

Titel

Drug Development for Gene Therapy : Translational Biomarkers, Bioanalysis, and Companion Diagnostics

Auflage

1st ed

Ort / Verlag

Newark : John Wiley & Sons, Incorporated,

Erscheinungsjahr

2024

Link zum Volltext

• Wiley Online Library - AutoHoldings Books

Beschreibungen/Notizen

• Cover -- Title Page -- Copyright Page -- Contents -- List of Contributors -- Preface -- Section I Introduction -- 1 Introduction to AAV-based in vivo Gene Therapy -- 1.1 Introduction -- 1.1.1 History of Gene Therapy -- 1.1.2 AAV-based in vivo Gene Therapy: A Revolution in Medicine -- 1.1.3 The AAV Vector Structure -- 1.1.4 Cell Entry and Transduction Pathway -- 1.2 Advantages and Disadvantages for AAV in vivo -- 1.2.1 Effectiveness and Advantages of AAV Vectors for in vivo Gene Therapy -- 1.2.2 Challenges of AAV Vectors for in vivo Gene Therapy -- 1.3 Technology Platforms of AAV-based in vivo Gene Therapy -- 1.3.1 cDNA Replacement -- 1.3.2 Genome Editing -- 1.3.2.1 ZFN -- 1.3.2.2 TALENs -- 1.3.2.3 CRISPR/Cas9 -- 1.3.3 Base Editing and Prime Editing -- 1.3.4 RNAi Gene Silencing -- 1.3.5 Gene Addition -- 1.4 AAV Serotypes and Tissue Affinity -- 1.4.1 The Liver as a Biofactory -- 1.4.2 The CNS as a Biofactory -- 1.4.3 The Muscle as a Biofactory -- 1.5 Precision Medicine: Screening and Monitoring Biomarkers, Companion Diagnostics -- 1.5.1 Gene Therapy Clinical Trials: Spotlight on Hemophilia A -- 1.6 Predictions for Scientific and Medical Progress -- 1.6.1 Predictions for Challenges in the Field -- 1.6.2 Addressing Durability -- 1.6.3 Addressing Immunogenicity -- 1.6.4 Addressing Malignancy -- 1.7 Predictions for Market Adoption -- 1.7.1 Patients and Patient Advocacy Groups -- 1.7.2 Physicians, Clinical Guidelines, Regulatory Agencies -- 1.7.3 Payers -- 1.8 Final Thoughts -- 1.8.1 Can We Afford in vivo Gene Therapies? -- 1.8.2 Can in vivo Gene Editing Replace Gene Therapy? -- References -- 2 Recent Development in in vivo Clinical Gene Therapy Platforms -- 2.1 Introduction -- 2.1.1 rAAV-cDNA Replacement Therapies -- 2.1.1.1 Introduction: Approved rAAV-cDNA Replacement Therapies -- 2.1.1.2 Glybera (alipogene tiparvovec), Marketed by uniQure.
• 2.1.1.3 Luxturna (voretigene neparvovec-rzyl), Marketed by Spark Therapeutics -- 2.1.1.4 Zolgensma (onasemnogene abeparvovec), Marketed by Novartis -- 2.1.2 Introduction: rAAV-cDNA (gene) Therapy Candidates in Clinical Development -- 2.1.2.1 AAV-Gene Replacement Clinical Trials for the Eye -- 2.1.2.2 Clinical Trials for Heart Disease -- 2.1.2.3 Clinical Trials for Hematologic and Metabolic Disease (Targeting the Liver) -- 2.1.2.4 Clinical Trials for Skeletal Muscle -- 2.1.3 Introduction: rAAV-as a Vehicle for in vivo Gene Editing -- 2.1.3.1 Non-nuclease Mediated Methods -- 2.1.3.2 Nuclease-mediated Homology Directed Repair -- 2.1.4 Nuclease-mediated Gene Disruption following AAV Delivery -- 2.1.5 Challenges and Opportunities with AAV as a Delivery Vehicle for Nuclease-Mediated Gene Editing -- References -- Section II Translational Biomarkers for Gene Therapy -- 3 Biomarker and Bioanalytical Readouts for the Development of AAV Gene Therapy -- 3.1 Introduction -- 3.1.1 AAV-Mediated in vivo Gene Therapy -- 3.1.2 Biomarker Category and Utility -- 3.2 Pharmacokinetic (PK) and Pharmacodynamic (PD) Biomarkers -- 3.2.1 Viral Biodistribution and Shedding -- 3.2.2 Transgene mRNA Expression -- 3.2.3 Transgene and Target Protein Activity and Concentration -- 3.2.4 Substrate and Other Distal PD Biomarkers -- 3.3 Safety and Monitoring Biomarkers and Readouts -- 3.3.1 Assessment of genotoxicity -- 3.3.1.1 AAV Integration/Insertional Mutagenesis Risk -- 3.3.1.2 AAV Germline Transmission Risk -- 3.3.1.3 Off-Target Gene Editing -- 3.3.2 Biomarkers for Immune-Mediated Toxicity -- 3.3.2.1 Hepatotoxicity -- 3.3.2.2 Thrombotic Microangiopathy -- 3.3.2.3 Muscle Toxicity -- 3.3.2.4 Immunogenicity Assessment for rAAV Gene Therapy -- 3.3.3 Safety Biomarkers for Nonimmune Organ-Specific Toxicity -- 3.3.3.1 Dorsal Root Ganglia Toxicity.
• 3.3.3.2 Other Target Organ Toxicity Biomarkers -- 3.4 Predictive and Diagnostic Biomarkers for Study Enrollment and Patient Stratification -- 3.4.1 Preexisting Anti-Capsid Antibody -- 3.4.1.1 Companion Diagnostic -- 3.4.2 Preexisting Anti-Transgene Protein Antibody -- 3.5 Summary -- References -- 4 Nonclinical and Clinical Study Considerations for Biodistribution, Shedding, and Pharmacokinetics/Pharmacodynamics -- 4.1 Biodistribution and Viral Shedding -- 4.1.1 Introduction to Biodistribution and Viral Shedding -- 4.1.1.1 Definition and Terminology for Biodistribution and Shedding -- 4.1.1.2 Global Regulatory Guidance on Conducting Biodistribution and Shedding Studies -- 4.1.2 Nonclinical Biodistribution and Shedding Studies for AAV Vectors -- 4.1.2.1 Design, Execution, and Reporting -- 4.1.2.2 Examples -- 4.1.3 Clinical Biodistribution and Shedding Studies for AAV Vectors -- 4.1.3.1 General Considerations in Viral Shedding Studies in the Clinical Setting -- 4.1.3.2 Biodistribution Characterization in Human: Necessity and Concerns -- 4.1.3.3 Examples -- 4.1.4 Gaps and Challenges on Biodistribution and Shedding Characterization -- 4.2 Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Clinical Dose Selection of Gene Therapy -- 4.2.1 Overview on PK/PD and Dose Selection Strategies for Gene Therapy -- 4.2.1.1 AAV Dosing Regimen - Safety Relationship and Safety-based Clinical Dose Projection -- 4.2.1.2 AAV Dose - Pharmacodynamics/Efficacy Relationship and Projection of Pharmacologically-Active Dose (PAD) -- 4.2.2 Dose Scaling Approaches: Allometric and Activity-Based Methods -- 4.2.3 Mechanistic Approaches to Modeling Gene Therapy -- 4.2.3.1 Modeling and Simulation of AAV Biodistribution -- 4.2.3.2 Modeling Transgene Product PK and PD of the Transgene Product -- 4.2.4 Clinical Pharmacology Considerations for Gene Therapy.
• 4.2.4.1 Variability in Transgene Product Levels and/or Treatment Response -- 4.2.4.2 Durability of Transgene Expression and/or Treatment Response -- 4.2.5 Gaps and Challenges on PK/PD and Clinical Dose Selection -- 4.2.5.1 Interspecies difference in AAV Transduction and Immunogenicity -- 4.2.5.2 Availability of Clinical Samples and Bioanalytical Assays -- 4.2.5.3 Availability of Long-Term Follow-Up Data -- 4.3 Summary -- References -- 5 Immunogenicity of AAV Gene Therapy Products -- 5.1 Innate and Adaptive Immunity Induced by AAV-Based Gene Therapies -- 5.1.1 Innate Immune Response -- 5.1.2 Adaptive Immune Response -- 5.2 Preclinical Immunogenicity Risk Assessment -- 5.2.1 Product-related Risk Factors -- 5.2.2 Process and Manufacturing-Related Risk Factors -- 5.2.3 Patient-Related Risk Factors -- 5.2.4 Nonclinical Assessment of Immunogenicity -- 5.2.5 Animal Models for Assessing Innate Immunity -- 5.2.6 Animal Models for Assessing Adaptive Immunity -- 5.2.7 Impact of Immunogenicity on Animal Selection and Interpretation of Study Results -- 5.3 Clinical Manifestation Associated with Immunogenicity -- 5.3.1 Pre-existing Immunity Against AAV Vector May Compromise Therapeutic Efficacy and Patient Safety -- 5.3.2 Treatment Induced Anti-AAV Capsid Antibodies May Prevent Re-dosing -- 5.3.3 Antibody Specific to Transgene Protein Could Lead to Toxicity or Unwanted Immunity -- 5.3.4 Risk of Immunogenicity Associated with Different Administration Routes -- 5.3.4.1 Gene Delivery to the Eye or Central Nervous System -- 5.3.4.2 Gene Delivery to Liver -- 5.3.4.3 Gene Delivery to Muscle -- 5.3.5 Product- and Process-related Impurity Related Immunogenicity -- 5.4 Clinical Mitigation Strategy -- References -- Section III Bioanalysis for Gene Therapy.
• 6 Bioanalytical Methods to Detect Preexisting and Post-administration Humoral Immune Responses Against AAV Capsid Proteins -- 6.1 Introduction -- 6.2 Considerations for AAV Total Antibody Assays -- 6.2.1 Nature of AAV TAb Assay Analyte -- 6.2.2 Primary Analytical Methodologies applied for AAV TAb Detection -- 6.2.3 Tab Assay Critical Reagent Considerations -- 6.2.3.1 Positive and Negative Control Selection -- 6.2.3.2 Capture and Detection Reagents -- 6.2.3.3 Sample Testing Strategy -- 6.2.4 Key Assay Qualification/Validation Parameters -- 6.2.4.1 Assay Sensitivity -- 6.2.4.2 Serotype Specificity -- 6.2.4.3 Precision -- 6.2.4.4 Matrix Interference and Selectivity -- 6.2.4.5 Assay Cut-Point -- 6.2.5 TAb Assay Data Interpretation -- 6.3 Considerations for Cell-based Transduction Inhibition Assays -- 6.3.1 Principle and Methodology of Cell-based AAV TI Assays -- 6.3.2 AAV TI Assay Development: Designing for Clinical Relevance -- 6.3.3 Key Assay Validation Parameters -- 6.3.3.1 Screening and Titer Cut-Points -- 6.3.3.2 Limit of Detection -- 6.3.3.3 Precision -- 6.3.3.4 Specificity -- 6.3.3.5 Confirmatory Steps to Ensure Specific Detection of Neutralizing AAV Antibodies -- 6.3.3.6 Selectivity/Matrix Interference -- 6.3.3.7 Stability -- 6.3.4 Sample Testing Strategy and Monitoring Assay Performance -- 6.3.5 Data Interpretation: Preexisting TI Titer and Clinical Efficacy -- 6.3.6 Value and Challenges of Standardizing TAb and TI Assays -- References -- 7 Bioanalytical Methods to Study Biodistribution and Shedding of AAV-Based Gene Therapy Vectors -- 7.1 Introduction -- 7.2 Choice of Platform: qPCR vs. Digital PCR -- 7.3 Aspects of Method Development -- 7.4 Back-Calculation Formulas and Extraction Efficiency Assessments -- 7.5 Sensitivity Requirements -- 7.6 Specificity Requirements -- 7.7 Standard Curve Performance, Colinearity, Precision, and Accuracy.
• 7.8 Selectivity Assessment and Matrix Interference.
• Description based on publisher supplied metadata and other sources.