Human Gene Therapy

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Challenges in Bringing Gene Therapy to the Market

 

 

 

 

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Advances and Challenges in Gene Therapy for Rare Diseases

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Design of Experiment (DoE) Based Optimization of Full AAV Particle Enrichment Using Stunner® as a High-Throughput Analysis Tool

Packaging heterogeneity in recombinant adeno-associated virus (rAAV) manufacturing may lead to potential product-related impurities like "empty" capsids, capsids containing partial vector genomes, and capsids containing different DNA impurities. It is technically very challenging to reduce or eliminate "empty" capsids in downstream processing, especially in a scalable manner. Here we describe a fully scalable method to efficiently enrich the percentage of full capsids by anion exchange chromatography.   

An anion exchange (AEX) chromatography step was established in isocratic elution mode and optimized by design of experiment (DoE) studies. DoE data were evaluated measuring the percentage-"full" and the vg-recovery of the enriched eluate by Stunner® (Unchained Labs). Stunner was the analysis-tool of choice for this study due to its high accuracy and speed for generating the DoE response data. DoE center point run results were confirmed using additional techniques.  

Based on the DoE studies it was determined that the capsid load and salt concentration during the empty particle elution phase are the most critical process parameters to achieve a high percentage of full particles and a satisfactory yield. The enrichment factor in fold-enrichment was investigated and found to depend on the proportion of "full" and "empty" capsids in the load material. For our optimized conditions we obtained an up to three-fold enrichment of full capsids compared to input material. 

The AEX chromatography process is designed to be optionally plugged into downstream processing depending on required product specifications. It is readily scalable and is a tool that can be adapted for specific expression cassettes or capsids. In this case, the salt concentrations could be adapted, and an identical DSP work package applied, all within two weeks using Stunner.

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Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease

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Gene Therapy Targeting the Brain Vasculature

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Gene Supplementation in Mice Heterozygous for the D477G RPE65 Variant Implicated in Autosomal Dominant Retinitis Pigmentosa  

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Application of Size Exclusion Chromatography with Multiangle Light Scattering in the Analytical Development of a Preclinical Stage Gene Therapy Program

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Assessment of Pre-Clinical Liver Models Based on Their Ability to Predict the Liver-Tropism of Adeno-Associated Virus Vectors

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Characterization of a Bioengineered AAV3B Capsid Variant with Enhanced Hepatocyte Tropism and Immune Evasion  

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Successfully Navigating Food and Drug Administration Orphan Drug and Rare Pediatric Disease Designations for AAV9-hPCCA Gene Therapy: The National Institutes of Health Platform Vector Gene Therapy Experience

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Neonatal Fc Receptor Inhibition Enables Adeno-Associated Virus Gene Therapy Despite Pre-Existing Humoral Immunity

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Pancreatic Cancer Cell and Gene Biotherapies: Past, Present, and Future

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Safety of Intravenous Administration of an AAV8 Vector Coding for an Oxidation-Resistant Human a1-Antitrypsin for the Treatment of a1-Antitrypsin Deficiency

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Dexamethasone Enhances Transgene Expression When Administered After Gene Therapy

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Gene Therapy for the Treatment of Huntington’s Disease

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Determining the Minimally Effective Dose for Gene Therapy in Hemophilia A

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Genome Editing to Treat Human Retinal Degeneration

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Biodistribution of AAV Gene Transfer Vectors in Nonhuman Primate

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Gene Therapy for Placental Insufficiency Moves Toward the Clinic

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AAV Capsid-Promoter Interactions in the Non-Human Primate Brain

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NIH Gene Therapy Startup to Increase AAV Gene Therapy Efficiency

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Risk of AAV Mobilization in Gene Therapy

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Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair

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Treating Cystic Fibrosis with mRNA Therapy or CRISPR

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Gene Therapy Corrects the Cardiac Effects of Friedreich’s Ataxia

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Toxicity of Dorsal Root Ganglia Is Widely Associated with CNS AAV Gene Therapy

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Engineered Capsids for Efficient Gene Delivery to the Eye

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New Human Gene Therapy Editorial: Concern and Next Steps Following Gene Therapy Adverse Events

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Benefiting from the National Gene Vector Biorepository

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Tracking Adeno-Associated Virus Capsid Evolution

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Gene Therapy Prevents Chronic Disorders Associated with Alcohol Exposure in ALDH2 Deficiency

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Mayo Clinic Researchers Test Novel Injection of Gene Therapy Vectors Directly into the Kidney

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Delivering Large Genes to the Retina is Problematic

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Progressing Toward Successful Gene-Based Approaches to Inherited Neurometabolic Diseases

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New AAV9 Gene Therapy Vector Dramatically Increases Life Span in Krabbe Disease Mouse Model

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Researchers Report Longest Duration of Therapeutic Gene Expression Following Delivery into Spinal Canal

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Estimating the Efficacy and Cost of Curative Gene Therapy for Beta-Thalassemia

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New Study Confirms EpCAM as Promising Target for Cancer Immunotherapy

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Urocortin 3 Gene Therapy Increases Systolic and Diastolic Function in Heart Failure

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Combination Gene Therapy More Effective in Cartilage Preservation In Moderate and Severe Osteoarthritis

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Advantages of DNA Immunization Platform for Eliciting Monoclonal Antibodies in Multiple Species

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Novel DNA Vaccine Design Based on Micro-Consensus Sequences Offers Broad Protection Against Influenza-A H3N2

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Is the End of the Recombinant DNA Advisory Committee (RAC) a Good Thing?

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Promising Results Support Continued Development of AAV-Based Human Factor VIII Gene Therapy

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Longest Reported Efficacy and Safety of AAV5-Based Gene Therapy to Treat Day Blind Sheep with Achromatopsia

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Single Injection of Novel Gene Therapy Vector Prolonged Survival in Mouse Model of Pompe Disease

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Researchers Show CRISPR Genome Editing Technology Can Correct Alpha-1 Antitrypsin Deficiency

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Researchers Describe Stem Cell-Derived Organoids for Testing Therapeutic Gene Delivery to Retinal and Photoreceptor Cells

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Interview with CAR T Cell Expert Dr. Michel Sadelain in Human Gene Therapy

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Gene Therapy for Lipoprotein Lipase Deficiency Yields Promising Results

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Genetically Modified Cornea Can Safely and Effectively Prevent Rejection Following Transplantation in High Risk Model

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New Work from Ron Crystal's Lab on Treating Hereditary Adrenal Disorders

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ZMapp Antibody Delivered by Viral Vector Protects Against Ebola Infection

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Chinese Research Advances Highlighted in Special Issue of Human Gene Therapy

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New Study Shows Severe Toxicity with High-Dose AAV9-Based Gene Therapy in Animal Models

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Gene Delivery of Drugs Directly into Arthritic Joints Is Making the Leap to Patients

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Inflammatory Factors Linked to Inhibition of Factor VIII Gene Therapy in Hemophilia A

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German Research Advances in Cancer and Blood Disorders Reported in Human Gene Therapy

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Researchers Use Mini Form of Replacement Gene to Delay Photoreceptor Degeneration in Leber Congenital Amaurosis

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New Gene Delivery Approach Could Allow Long-Term Persistence in Proliferating Cells

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New Study Shows Promise of Gene Therapy to Treat Alcoholism

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Mesenchymal Stem Cells Offer Novel Treatment Approach for Crohn's Disease Fistula

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Researchers Describe Novel Reporter Proteins for Tracking Long Term Expression of Therapeutic Genes

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Intranasal Gene Delivery: Noninvasive Approach Shows Efficacy for Preventing Neurologic Effects of Inherited Metabolic Disease

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Prednisone May Improve Effectiveness of AAV-Based Gene Therapy by Reducing Immune Response

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Safety of Gene Transfer to Treat Heart Failure Supports Further Clinical Development

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What Causes Gene Transfer to Trigger T Cell Activation and Exhaustion?

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New Studies Refocus Attention on the Genotoxicity of Adeno-associated Viral Vectors in Gene Therapy

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Debate Continues Over Human Immune System's Role in Blocking Therapeutic Genes Delivered Using AAV Vectors

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Researchers Improve Vectors for Delivering Human Factor VIII Gene Therapy to Treat Hemophilia A

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Will AAV Vectors Have a Role in Future Novel Gene Therapy Approaches?

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Feng Zhang Discusses CRISPR and Future of Gene Editing in Interview in Human Gene Therapy

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AAV Gene Delivery Vectors and Cancer -- The Debate Continues

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New Approach to Improve Therapeutic Gene Delivery to Arthritic Joints

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New system for Therapeutic Gene Delivery Increases Transgene Expression up to 100-fold

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Gene Delivery to the Lung Can Treat Broad Range of Diseases Within and Beyond the Lung

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Katherine High Talks Gene Therapy Progress for Hemophilia & Inherited Retinopathies

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Gene Therapy for Liver Disease Advancing With the Help of Adenoassociated Viral Vectors

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Gene Therapy to Prevent Vision Loss: Studies in Primates Needed to Optimize Human Trials