scholarly journals The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-8
Author(s):  
Valeria Roca ◽  
Juan Cruz Casabona ◽  
Pablo Radice ◽  
Verónica Murta ◽  
Fernando Juan Pitossi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Substantia Nigra Pars Compacta ◽  
Putative Gene ◽  
Inflammatory Stimuli ◽  
Therapy Interventions

Parkinson's disease (PD) is characterized by the progressive degeneration of neurons in the substantia nigra pars compacta (SN). The naïve SN is highly susceptible to inflammation. In addition, microglial activation in the degenerating SN displays distinct characteristics that increase the reactivity of the region towards inflammatory stimuli. On the other hand, gene therapy for PD has recently move forward into clinical settings, with PD being the neurodegenerative disorder with the highest number of Phase I/II gene therapy clinical trials approved and completed. These clinical trials are not targeting the SN, but this region is a certain candidate for future gene therapy interventions. Here, the unique immune-related properties of the degenerating SN in the context of a putative gene therapy intervention are reviewed. Several variables affecting the host response to gene delivery such as vector type and dosage, age and stage of disease of patients, and method of gene delivery and transgene used are discussed. Finally, approaches to diminish the risk of immune-mediated toxicity by gene transfer in the SN are presented.

Gene therapy for Parkinson's disease

2004 ◽  
Vol 6 (5) ◽  
pp. 1-18 ◽  
Author(s):  
Patricia A. Lawlor ◽  
Matthew J. During
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Gene Transfer ◽  
Neurodegenerative Disorder ◽  
Single Gene ◽  
Neuronal Population ◽  
Substantia Nigra Pars Compacta ◽  
Current Standard ◽  
Transfer Strategies

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.

scholarly journals Light-induced adenovirus gene transfer, an efficient and specific gene delivery technology for cancer gene therapy

2002 ◽  
Vol 9 (4) ◽  
pp. 365-371 ◽  
Author(s):  
Anders Høgset ◽  
Birgit Øvstebø Engesæter ◽  
Lina Prasmickaite ◽  
Kristian Berg ◽  
Øystein Fodstad ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Cancer Gene Therapy ◽  
Specific Gene ◽  
Cancer Gene ◽  
Delivery Technology

Adeno-Associated Viral Vectors for Gene Transfer and Gene Therapy

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
H. Büeler
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Adeno Associated Virus ◽  
Viral Genes ◽  
Virus Recombinant

AbstractAdeno-associated virus (AAV) is a defective, non-pathogenic human parvovirus that depends for growth on coinfection with a helper adenovirus or herpes virus. Recombinant adeno-associated viruses (rAAVs) have attracted considerable interest as vectors for gene therapy. In contrast to other gene delivery systems, rAAVs lack all viral genes and show long-term gene expression

scholarly journals Pharmacological, Cell, and Gene Therapy Strategies to Promote Spinal Cord Regeneration

2002 ◽  
Vol 11 (6) ◽  
pp. 593-613 ◽  
Author(s):  
Bas Blits ◽  
Gerard J. Boer ◽  
Joost Verhaagen
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Nervous System ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Cell Transplantation ◽  
Ex Vivo ◽  
Neuronal Survival ◽  
Genetically Modified ◽  
Injured Spinal Cord

In this review, recent studies using pharmacological treatment, cell transplantation, and gene therapy to promote regeneration of the injured spinal cord in animal models will be summarized. Pharmacological and cell transplantation treatments generally revealed some degree of effect on the regeneration of the injured ascending and descending tracts, but further improvements to achieve a more significant functional recovery are necessary. The use of gene therapy to promote repair of the injured nervous system is a relatively new concept. It is based on the development of methods for delivering therapeutic genes to neurons, glia cells, or nonneural cells. Direct in vivo gene transfer or gene transfer in combination with (neuro)transplantation (ex vivo gene transfer) appeared powerful strategies to promote neuronal survival and axonal regrowth following traumatic injury to the central nervous system. Recent advances in understanding the cellular and molecular mechanisms that govern neuronal survival and neurite outgrowth have enabled the design of experiments aimed at viral vector-mediated transfer of genes encoding neurotrophic factors, growth-associated proteins, cell adhesion molecules, and antiapoptotic genes. Central to the success of these approaches was the development of efficient, nontoxic vectors for gene delivery and the acquirement of the appropriate (genetically modified) cells for neurotransplantation. Direct gene transfer in the nervous system was first achieved with herpes viral and E1-deleted adenoviral vectors. Both vector systems are problematic in that these vectors elicit immunogenic and cytotoxic responses. Adeno-associated viral vectors and lentiviral vectors constitute improved gene delivery systems and are beginning to be applied in neuroregeneration research of the spinal cord. Ex vivo approaches were initially based on the implantation of genetically modified fibroblasts. More recently, transduced Schwann cells, genetically modified pieces of peripheral nerve, and olfactory ensheathing glia have been used as implants into the injured spinal cord.

scholarly journals Enhancement of Muscle Gene Delivery with Pseudotyped Adeno-Associated Virus Type 5 Correlates with Myoblast Differentiation

2001 ◽  
Vol 75 (16) ◽  
pp. 7662-7671 ◽  
Author(s):  
Dongsheng Duan ◽  
Ziying Yan ◽  
Yongping Yue ◽  
Wei Ding ◽  
John F. Engelhardt
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Muscle Cells ◽  
Therapeutic Benefit ◽  
Transduction Efficiency ◽  
Great Promise ◽  
Adeno Associated Virus ◽  
Muscle Gene ◽  
Duchenne's Muscular Dystrophy

ABSTRACT Adeno-associated virus (AAV)-based muscle gene therapy has achieved tremendous success in numerous animal models of human diseases. Recent clinical trials with this vector have also demonstrated great promise. However, to achieve therapeutic benefit in patients, large inocula of virus will likely be necessary to establish the required level of transgene expression. For these reasons, efforts aimed at increasing the efficacy of AAV-mediated gene delivery to muscle have the potential for improving the safety and therapeutic benefit in clinical trials. In the present study, we compared the efficiency of gene delivery to mouse muscle cells for recombinant AAV type 2 (rAAV-2) and rAAV-2cap5 (AAV-2 genomes pseudo-packaged into AAV-5 capsids). Despite similar levels of transduction by these two vectors in undifferentiated myoblasts, pseudotyped rAAV-2cap5 demonstrated dramatically enhanced transduction in differentiated myocytes in vitro (>500-fold) and in skeletal muscle in vivo (>200-fold) compared to rAAV-2. Serotype-specific differences in transduction efficiency did not directly correlate with viral binding to muscle cells but rather appeared to involve endocytic or intracellular barriers to infection. Furthermore, application of this pseudotyped virus in a mouse model of Duchenne's muscular dystrophy also demonstrated significantly improved transduction efficiency. These findings should have a significant impact on improving rAAV-mediated gene therapy in muscle.

scholarly journals Platelet-Targeted Gene Transfer Induces Antigen-Specific Immune Tolerance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2154-2154
Author(s):  
Luo Xiaofeng ◽  
Jocelyn A. Schroeder ◽  
Christina Baumgartner ◽  
Juan Chen ◽  
Jianda Hu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Immune Tolerance ◽  
Transgene Expression ◽  
Tolerance Induction ◽  
Control Group ◽  
Specific Gene ◽  
Hematopoietic Stem ◽  
Immune Tolerance Induction

Abstract Induction of antigen-specific immune tolerance is desirable in autoimmune diseases, transplantation, and gene therapy. Our previous studies have demonstrated that FVIII or FIX expression ectopically targeted to platelets under control of the platelet-specific αIIb promoter results in transgene protein storage in platelet α-granules. Further studies have demonstrated that lentivirus-mediated platelet-specific gene delivery to hematopoietic stem cells (HSCs) not only restores hemostasis but also induces antigen-specific immune tolerance in hemophilic mice. We wanted to explore whether platelet-specific gene transfer can be used as a means of immune tolerance induction. In the current study, we used ovalbumin (OVA) as a non-coagulant protein to further examine the potential of a platelet gene therapy-based immune tolerance induction approach. We constructed a lentiviral vector (LV) in which OVA is driven by the αIIb promoter (2bOVA). Evidence suggests that VWF propeptide can reroute unrelated secreting proteins to a storage pathway. Thus, we designed another vector, 2bVpOVA, which contains VWF propeptide to secure OVA storage in platelet granules. HSCs from wild type B6/CD45.2 mice were transduced with 2bOVA or 2bVpOVA LV and transplanted into B6/CD45.1 recipients preconditioned with 660 cGy total body irradiation. We found that 96% of OVA expression in whole blood was stored in platelets with a level of 51.3 ± 22.5 ng/108 platelets (n = 5) while 4% was detectable in plasma in 2bOVA-transduced recipients at 12-week after transplantation. This distribution is very similar to the results we obtained from the FIX study. In contrast, 98% of OVA was stored in platelets with a level of 3.9 ± 3.3 ng/108 platelets (n = 5) in 2bVpOVA-transduced recipients. The lower total OVA expression level in the 2bVpOVA group could be due to the size effect of transgene expression cassette as the 2bVpOVA cassette is 3-fold larger than the 2bOVA cassette. To investigate whether anti-OVA immune tolerance was established in recipients after platelet-specific OVA gene transfer, 16-weeks post-transplantation, animals were challenged with OVA. The titer of anti-OVA total IgG determined by ELISA assay was 640 ± 101 in the 2bOVA group and 320 ± 0 in the 2bVpOVA group. These titers were significantly lower than that obtained from the untransduced control group (10210 ± 3636), demonstrating that platelet-specific OVA gene delivery to HSCs can suppress the anti-OVA immune response. Of note, the titer of anti-OVA total IgG in the 2bVpOVA group was significantly lower than in the 2bOVA group although the total OVA expression levels in the 2bOVA group is 13-fold higher than in the 2bVpOVA group. The percentage of regulatory T cells in peripheral blood in 2bOVA and 2bVpOVA-transduced recipients was significantly higher than in untransduced control animals. In summary, our data demonstrate that targeting transgene expression and storage in platelet a-granules is a potentially promising approach for inducing immune tolerance. Disclosures No relevant conflicts of interest to declare.

Combined Analysis of Clinical Data on HGF Gene Therapy to Treat Critical Limb Ischemia in Japan

2020 ◽  
Vol 20 (1) ◽  
pp. 25-35 ◽  
Author(s):  
Ryuichi Morishita ◽  
Munehisa Shimamura ◽  
Yasushi Takeya ◽  
Hironori Nakagami ◽  
Mitsuaki Chujo ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Placebo Group ◽  
Gene Transfer ◽  
Critical Limb Ischemia ◽  
Therapy Group ◽  
Limb Ischemia ◽  
Open Trial ◽  
Combined Analysis ◽  
Ischemic Ulcer

Objectives: The objective of this combined analysis of data from clinical trials in Japan, using naked plasmid DNA encoding hepatocyte growth factor (HGF), was to document the safety and efficacy of intramuscular HGF gene therapy in patients with critical limb ischemia (CLI). Methods: HGF gene transfer was performed in 22 patients with CLI in a single-center open trial at Osaka University; 39 patients in a randomized, placebo-controlled, multi-center phase III trial, 10 patients with Buerger’s disease in a multi-center open trial; and 6 patients with CLI in a multi-center open trial using 2 or 3 intramuscular injections of naked HGF plasmid at 2 or 4 mg. Resting pain on a visual analogue scale (VAS) and wound healing as primary endpoints were evaluated at 12 weeks after the initial injection. Serious adverse events caused by gene transfer were detected in 7 out of 77 patients (9.09%). Only one patient experienced peripheral edema (1.30%), in contrast to those who had undergone treatment with VEGF. At 12 weeks after gene transfer, combined evaluation of VAS and ischemic ulcer size demonstrated a significant improvement in HGF gene therapy group as compared to the placebo group (P=0.020). Results: The long-term analysis revealed a sustained decrease in the size of ischemic ulcer in HGF gene therapy group. In addition, VAS score over 50 mm at baseline (total 27 patients) demonstrated a tendency (P=0.059), but not significant enough, to improve VAS score in HGF gene therapy as compared to the placebo group. Conclusions: The findings indicated that intramuscular injection of naked HGF plasmid tended to improve the resting pain and significantly decreased the size of the ischemic ulcer in the patients with CLI who did not have any alternative therapy, such as endovascular treatment (EVT) or bypass graft surgery. An HGF gene therapy product, CollategeneTM, was recently launched with conditional and time-limited approval in Japan to treat ischemic ulcer in patients with CLI. Further clinical trials would provide new therapeutic options for patients with CLI.

scholarly journals Pesticides and Parkinson’s Disease

2001 ◽  
Vol 1 ◽  
pp. 207-208 ◽  
Author(s):  
Todd B. Sherer ◽  
Ranjita Betarbet ◽  
J. Timothy Greenamyre
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Selective Death ◽  
Underlying Mechanisms ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

Gene Transfer Using Nonviral Delivery Systems

2006 ◽  
Vol 26 (6) ◽  
pp. 633-640 ◽  
Author(s):  
Masanobu Miyazaki ◽  
Yoko Obata ◽  
Katsushige Abe ◽  
Akira Furusu ◽  
Takehiko Koji ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Peritoneal Dialysis ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Delivery System ◽  
Viral Vectors ◽  
Nonviral Vectors ◽  
Gene Delivery System ◽  
Peritoneal Membrane ◽  
Peritoneal Function

In peritoneal dialysis, loss of peritoneal function is a major factor in treatment failure. The alterations in peritoneal function are related to structural changes in the peritoneal membrane, including peritoneal sclerosis with increased extracellular matrix. Although peritoneal sclerosis is considered reversible to some extent through peritoneal rest, which improves peritoneal function and facilitates morphological changes, there has been no therapeutic intervention and no drug against the development and progression of peritoneal sclerosis. Using recent biotechnological advances in genetic engineering, a strategy based on genetic modification of the peritoneal membrane could be a potential therapeutic maneuver against peritoneal sclerosis and peritoneal membrane failure. Before this gene therapy may be applied clinically, a safe and effective gene delivery system as well as the selection of a gene therapy method must be established. There are presently two kinds of gene transfer vectors: viral and nonviral. Viral vectors are used mainly as a gene delivery system in the field of continuous ambulatory peritoneal dialysis research; however, they have several problems such as immunogenicity and toxicity. On the other hand, nonviral vectors have several advantages over viral vectors. We review here gene transfer using nonviral vector systems in the peritoneum: electroporation, liposomes, and cationized gelatin microspheres. In the field of peritoneal dialysis, gene therapy research using nonviral vectors is presently limited. Improvement in delivery methods together with an intelligent design of targeted genes has brought about large degrees of enhancement in the efficiency, specificity, and temporal control of nonviral vectors.

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