Abstract
Glial cell line-derived neurotrophic factor (GDNF) family of ligands (GDFLs) as well as other trophic factors have, in animal models of Parkinsons disease (PD), demonstrated the potential for excellent ameliorative properties. Clinical trials that have mechanically injected GDNF intracerebrally, while demonstrating relative safety, have been clinically disappointing to date. Likewise, recombinant adeno-associated virus (rAAV) delivered neurturin (cere-120) has also been demonstrated to be safe in humans, however clinical results have been negative. The failure of the major clinical trials has cast some doubt in the field about trophic factor delivery for the treatment of PD. In this review, we make the case that GDFLs are likely to function only when there are remaining dopamine neurons in the nigrostriatal pathway as opposed to other candidate modes of action. Thus, it is our view that utilizing earlier stage PD patients who have significant nigrostriatal dopamine innervation remaining would be more ideal to demonstrate the efficacy of GDFLs. This is particularly true when considering a novel delivery method such as gene transfer. However, if earlier stage patients are to be enrolled in GDFL gene transfer trials, then a much better safety profile must be demonstrated by preclinical experiments. One important safety advance might be the use of an external regulation system to control the expression level of the transgene. However, gene regulation systems pose unique safety issues and we will discuss these in detail. It is our view that GDFLs still remain as a promising therapeutic approach for PD.
Current Gene Therapy
Title: Gene Therapy for Neurological Disorders: Challenges and Future Prospects for the Use of Growth Factors for the Treatment of Parkinsons Disease
Volume: 9 Issue: 5
Author(s): Fredric p. Manfredsson, Michael S. Okun and Ronald J. Mandel
Affiliation:
Abstract: Glial cell line-derived neurotrophic factor (GDNF) family of ligands (GDFLs) as well as other trophic factors have, in animal models of Parkinsons disease (PD), demonstrated the potential for excellent ameliorative properties. Clinical trials that have mechanically injected GDNF intracerebrally, while demonstrating relative safety, have been clinically disappointing to date. Likewise, recombinant adeno-associated virus (rAAV) delivered neurturin (cere-120) has also been demonstrated to be safe in humans, however clinical results have been negative. The failure of the major clinical trials has cast some doubt in the field about trophic factor delivery for the treatment of PD. In this review, we make the case that GDFLs are likely to function only when there are remaining dopamine neurons in the nigrostriatal pathway as opposed to other candidate modes of action. Thus, it is our view that utilizing earlier stage PD patients who have significant nigrostriatal dopamine innervation remaining would be more ideal to demonstrate the efficacy of GDFLs. This is particularly true when considering a novel delivery method such as gene transfer. However, if earlier stage patients are to be enrolled in GDFL gene transfer trials, then a much better safety profile must be demonstrated by preclinical experiments. One important safety advance might be the use of an external regulation system to control the expression level of the transgene. However, gene regulation systems pose unique safety issues and we will discuss these in detail. It is our view that GDFLs still remain as a promising therapeutic approach for PD.
Export Options
About this article
Cite this article as:
Manfredsson p. Fredric, Okun S. Michael and Mandel J. Ronald, Gene Therapy for Neurological Disorders: Challenges and Future Prospects for the Use of Growth Factors for the Treatment of Parkinsons Disease, Current Gene Therapy 2009; 9 (5) . https://dx.doi.org/10.2174/156652309789753400
DOI https://dx.doi.org/10.2174/156652309789753400 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
Call for Papers in Thematic Issues
Melatonin Signaling in Health and Disease
Melatonin regulates a multitude of physiological functions, including circadian rhythms, acting as a scavenger of free radicals, an anti-inflammatory agent, a modulator of mitochondrial homeostasis, an antioxidant, and an enhancer of nitric oxide bioavailability. AANAT is the rate-limiting enzyme responsible for converting serotonin to NAS, further converted to melatonin by ...read more
Programmed Cell Death Genes in Oncology: Pioneering Therapeutic and Diagnostic Frontiers (BMS-CGT-2024-HT-45)
Programmed Cell Death (PCD) is recognized as a pivotal biological mechanism with far-reaching effects in the realm of cancer therapy. This complex process encompasses a variety of cell death modalities, including apoptosis, autophagic cell death, pyroptosis, and ferroptosis, each of which contributes to the intricate landscape of cancer development and ...read more
Related Journals
![](/images/wayfinder.jpg)
- 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
-
The Etiology of Hypertension in the Metabolic Syndrome Part Four: The Systemic Perspective – The Role of the Neuroendocrine and Immune Systems,and the Challenge of Integration
Current Vascular Pharmacology Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core
Current Topics in Medicinal Chemistry Delayed Treatment with Nicotinamide Inhibits Brain Energy Depletion,Improves Cerebral Microperfusion, Reduces Brain Infarct Volume, but does not Alter Neurobehavioral Outcome Following Permanent Focal Cerebral Ischemia in Sprague Dawley Rats
Current Neurovascular Research Dysfunction of Endoplasmic Reticulum (ER) and Mitochondria (MT) in Alzheimer's Disease: The Role of the ER-MT Cross-Talk
Current Alzheimer Research β-Synuclein Assembly as a Therapeutic Target of Parkinsons Disease and Related Disorders
Current Pharmaceutical Design Update on Diagnostic and Treatment of Uncomplicated and Complicated Malaria in Adults and Selected Vulnerable Populations
Infectious Disorders - Drug Targets Potential of Bone Marrow Stromal Cells in Applications for Neuro-Degenerative, Neuro-Traumatic and Muscle Degenerative Diseases
Current Neuropharmacology The Concept of “Neuroprotection” in Neurological Diseases
Current Neuropharmacology Commentary [ Research Highlights(To miR or Not to miR: That is the Question in ALS Disease ]
CNS & Neurological Disorders - Drug Targets Inhibition of Sphingomyelin Hydrolysis: Targeting the Lipid Mediator Ceramide as a Key Regulator of Cellular Fate
Current Medicinal Chemistry Long-term Potentiation at Spinal C-fiber Synapses: A Target for Pathological Pain
Current Pharmaceutical Design Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS)
Current Neuropharmacology Antenatal Maternal Antidepressants Drugs Affect S100B Concentrations in Fetal-Maternal Biological Fluids
CNS & Neurological Disorders - Drug Targets Targeting NLRP3 Inflammasome: Structure, Function, and Inhibitors
Current Medicinal Chemistry Selective Divalent Copper Chelation for the Treatment of Diabetes Mellitus
Current Medicinal Chemistry Apelin/Apelin Receptor System: Molecular Characteristics, Physiological Roles, and Prospects as a Target for Disease Prevention and Pharmacotherapy
Current Molecular Pharmacology Combat Military Personnel and Selective Risk Factors for the Development of Dementias - A Review
Current Psychiatry Research and Reviews Initiation of the Immune Response by Extracellular Hsp72: Chaperokine Activity of Hsp72
Current Immunology Reviews (Discontinued) Anti-Inflammatory Iridoids of Botanical Origin
Current Medicinal Chemistry Hormone Replacement Therapy and Stroke
Current Vascular Pharmacology