Abstract
Hepatocytes are a key target for gene transfer directed at correction of inborn errors of metabolism. The theoretical potential of hepatocyte-directed gene transfer contrasts with the hurdles for clinical translation of this technology. Innate immune responses following gene transfer are initiated by recognition of pathogen-associated molecular patterns by pattern recognition receptors like Toll-like receptors. Adaptive immune responses may constitute the most significant hurdle for efficient gene transfer. Besides the challenge imposed by adaptive immune responses against the vector and the potential problem of pre-existing immunity, immune responses against the transgene product may also constitute an obstacle. The liver is a tolerogenic organ. Naive T cells encounter liver antigens initially in the liver, rather than in lymphoid tissue. Lymph nodes and the spleen are anatomical compartments that provide a particular microarchitecture and microenvironment for the induction of immunity. In contrast, antigen presentation in the liver takes place in a completely different microarchitecture and microenvironment. This is a key aspect of the hepatic adaptive immune tolerance induction. Consistent with the tolerogenic nature of the liver microenvironment, the risk of antibody formation against the transgene product may be limited in the setting of hepatocyte-directed gene transfer and specifically by restricting transgene expression to hepatocytes by use of hepatocyte-specific expression cassettes. However, it is unclear to which extent animal experimental data following gene transfer predict immune responses in humans. Extrapolations from animals to humans are required but should be performed with sufficient insight into the dramatic species differences of the immune system.
Keywords: gene therapy, gene transfer, innate immunity, tolerance, adaptive immunity, liver, Adenoviral vectors, Interleukin (IL)-6, macrophages, hepatocytes
Current Pharmaceutical Design
Title: Gene Transfer for Inherited Metabolic Disorders of the Liver: Immunological Challenges
Volume: 17 Issue: 24
Author(s): Stephanie C. Gordts, Eline Van Craeyveld, Frank Jacobs and Bart De Geest
Affiliation:
Keywords: gene therapy, gene transfer, innate immunity, tolerance, adaptive immunity, liver, Adenoviral vectors, Interleukin (IL)-6, macrophages, hepatocytes
Abstract: Hepatocytes are a key target for gene transfer directed at correction of inborn errors of metabolism. The theoretical potential of hepatocyte-directed gene transfer contrasts with the hurdles for clinical translation of this technology. Innate immune responses following gene transfer are initiated by recognition of pathogen-associated molecular patterns by pattern recognition receptors like Toll-like receptors. Adaptive immune responses may constitute the most significant hurdle for efficient gene transfer. Besides the challenge imposed by adaptive immune responses against the vector and the potential problem of pre-existing immunity, immune responses against the transgene product may also constitute an obstacle. The liver is a tolerogenic organ. Naive T cells encounter liver antigens initially in the liver, rather than in lymphoid tissue. Lymph nodes and the spleen are anatomical compartments that provide a particular microarchitecture and microenvironment for the induction of immunity. In contrast, antigen presentation in the liver takes place in a completely different microarchitecture and microenvironment. This is a key aspect of the hepatic adaptive immune tolerance induction. Consistent with the tolerogenic nature of the liver microenvironment, the risk of antibody formation against the transgene product may be limited in the setting of hepatocyte-directed gene transfer and specifically by restricting transgene expression to hepatocytes by use of hepatocyte-specific expression cassettes. However, it is unclear to which extent animal experimental data following gene transfer predict immune responses in humans. Extrapolations from animals to humans are required but should be performed with sufficient insight into the dramatic species differences of the immune system.
Export Options
About this article
Cite this article as:
C. Gordts Stephanie, Van Craeyveld Eline, Jacobs Frank and De Geest Bart, Gene Transfer for Inherited Metabolic Disorders of the Liver: Immunological Challenges, Current Pharmaceutical Design 2011; 17 (24) . https://dx.doi.org/10.2174/138161211797247604
DOI https://dx.doi.org/10.2174/138161211797247604 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Coated with Nanomaterials Intraocular Lenses, Ophthalmic and Human Body Implantable Devices with High Catalytic Antioxidant Activities: A New Nanotechnology Strategy of Peroxidase Cellular Enzyme Mimics Increasing the Biocompatibility and Therapeutic Deployment of the Medical Prosthetic Device
Recent Patents on Drug Delivery & Formulation Matricellular Proteins in Myocardial Infarction
Current Cardiology Reviews Confocal Laser Scanning Microscope, Raman Microscopy and Western Blotting to Evaluate Inflammatory Response after Myocardial Infarction
Current Vascular Pharmacology Editorial [Hot Topic: Matrix Metalloproteinases in Cardiovascular Disease (Guest Editors: N. Papageorgiou & D. Tousoulis)]
Current Topics in Medicinal Chemistry Clinical Applications for Cardiovascular Magnetic Resonance Imaging at 3 Tesla
Current Cardiology Reviews Autonomic Nervous System in Viral Myocarditis: Pathophysiology and Therapy
Current Pharmaceutical Design Endoplasmic Reticulum Stress as a Novel Therapeutic Target in Heart Diseases
Cardiovascular & Hematological Disorders-Drug Targets Targeted Nucleic Acid Delivery to Mitochondria
Current Gene Therapy Angiotensin Receptor Blockers in Chronic Heart Failure: Clinical Implications and Molecular Mechanisms
Current Cardiology Reviews Vitamin D and Vitamin D Receptor Activators in Treatment of Hypertension and Cardiovascular Disease
Cardiovascular & Hematological Disorders-Drug Targets Phytocompounds as Potential Agents to Treat Obesity-Cardiovascular Ailments
Cardiovascular & Hematological Agents in Medicinal Chemistry Hypertension and Angiogenesis
Current Pharmaceutical Design Editorial [Hot Topic:The Metabolic Treatment of Coronary Artery Disease and Heart Failure(Executive Editor: Pericle Di Napoli)]
Current Pharmaceutical Design Evaluation of Echocardiographic Abnormalities in HIV Positive Patients Treated with Antiretroviral Medications
Infectious Disorders - Drug Targets Gene Therapy for Lysosomal Storage Diseases: Progress, Challenges and Future Prospects
Current Pharmaceutical Design Diet-Derived Phytochemicals: From Cancer Chemoprevention to Cardio-Oncological Prevention
Current Drug Targets Therapeutic Angiogenesis using Hepatocyte Growth Factor (HGF)
Current Gene Therapy Peripheral Heart Blocks Associated with Myocardial Infarcts: Clinical Diagnosis Based on Experimental Findings
Current Cardiology Reviews The DOCA-Salt Hypertensive Rat as a Model of Cardiovascular Oxidative and Inflammatory Stress
Current Cardiology Reviews The Role of iNOS in Chronic Inflammatory Processes In Vivo: Is it Damage-Promoting, Protective, or Active at all?
Current Molecular Medicine