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At least 1,261 records · Page 70Linked to original sources
PubMed1999

Antisense inhibition of AT1 receptor in vascular smooth muscle cells using adeno-associated virus-based vector.

Vascular smooth muscle cells (VSMCs) are the main peripheral target for vasoconstriction and growth-promoting activity of angiotensin II (Ang II), acting through angiotensin type 1 receptors (AT1-R). Current antihypertension treatments include daily reductions in the effects of Ang II. To decrease an effect of Ang II in a prolonged fashion, we have developed an adeno-associated virus (AAV) vector with antisense DNA for AT1-R. AAV has many advantages over other viral vectors. AAV is nonpathogenic, does not stimulate inflammation or immune reaction and enters nondividing cells, and provides stable long-term gene expression. To test AAV in VSMCs, we constructed and tested plasmid AAV (pAAV) and recombinant AAV (rAAV) with AT1-R antisense DNA. rAAV was constructed with a cassette containing a cytomegalovirus promoter and the cDNA for the AT1-R inserted in the antisense direction. The cassette was packaged into the virion. Transfection of VSMCs with the pAAV antisense to AT1-R produced a significant reduction in the amount of AT1-R (P<0.01). Transduction of VSMCs with the rAAV-AT1-R-AS at MOI of 5 also showed significant reduction of AT1-R and long-lasting expression of the transgene for at least 8 weeks. The reduction of AT1-R number in VSMCs was concomitant with a decrease in the Ang II-stimulated increase of intracellular calcium. The results show that AAV vector delivers AT1-R antisense to inhibit AT1-R in VSMCs. For the purpose of gene therapy for hypertension, it is necessary to demonstrate the effectiveness of a vector system in VSMCs. This study provides support for the potential use of AAV AT1-R antisense in VSMCs.

Angiotensin II↗
PubMed2006

[Optimization of in-vivo gene transfer through regulating biological response to vectors].

The spatiotemporal distribution of transgenes determines the therapeutic efficacy of in vivo gene transfer. The important parameters of gene transfer are the level, duration, and cell specificity of expression, and the number of transfected cells. Interaction of vectors with blood cells, antigen-presenting cells, serum proteins, and other biological components affects the tissue distribution of vectors and the profile of transgene expression. Although plasmid DNA is less immunogenic than viral vectors, it can induce inflammatory cytokine release, due mainly to the presence of unmethylated CpG dinucleotides (CpG motifs). It was clearly demonstrated that intravenous injection of a plasmid DNA/cationic liposome complex resulted not only in the induction of inflammatory cytokines, but also in the activation of nuclear factor kappaB (NF-kappaB) in the lung. Insertion of additional NF-kappaB-binding sequences into conventional plasmid DNA resulted in a high transgene expression in the lung, suggesting that the biological response to vectors can be used to increase transgene expression. In a marked contrast to this strategy, long-term transgene expression was achieved by reducing the number of the CpG motifs in plasmid DNA. A plasmid encoding murine interferon (IFN)-beta or IFN-gamma with reduced numbers of CpG motifs was highly effective in inhibiting metastatic tumor growth in mice. These results clearly demonstrate the importance of the regulation of biological responses to plasmid vectors to optimize plasmid-based in vivo gene transfer.

Animals↗
PubMed2003

Molecular therapies for viral hepatitis.

Current treatment modalities available for hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are not efficient. The enormous disease burden caused by these two infections makes the development of novel therapies critical. For HCV, the development of an effective vaccine is urgent in view of the escalating number of infected individuals. Molecular therapies for HBV and HCV infection can be directed at reducing viral load by interfering with the life cycle of the viruses or at generating immune response against viral epitopes. The antiviral approaches consist of the delivery or expression of antisense RNAs, ribozymes or dominant negative proteins. Viral biology can be interrupted by attacking various potential targets within the two viruses. DNA-based vaccination strategies are being explored for both prevention and treatment of these diseases. Both non-viral and recombinant viral vectors are being developed for safe, effective and long-term gene transfer to the liver. Although no "ideal" vector is available at this time, the ingenuity of numerous investigators is leading to the improvement of the vector systems, promising successful application of gene therapy to the prevention and treatment of viral hepatitis in the foreseeable future.

Animals↗
PubMed2003

Therapeutic applications of human heme oxygenase gene transfer and gene therapy.

The search for methods to control physiological levels of carbon monoxide (CO), a vasoactive molecule, and bilibrubin, an antioxidant, have improved our understanding of the protective role of heme oxygenase (HO) against oxidative injury. HO activity can assist other antioxidant systems in diminishing the overall production of reactive oxygen species, thus contributing to cellular resistance to such injury. Overexpression of HO gene by targeted gene transfer has become a powerful tool for studying the role of this human enzyme. Successful and functional HO gene transfer requires two essential elements. First, the HO gene must be delivered into a safe vector, such as the adenoviral, retroviral and leptosome based vectors that are currently being used in clinical trials. The use of non-viral vectors has also been described. Second, with the exception of HO gene delivery to ocular or cardiovascular tissue via catheter-based interventions, HO gene delivery must be site and organ specific. Site-specific delivery of HO-1 to renal structures in SHR, specifically mTAL, using Na+-K+ Cl- cotransporter (NKCC2 promoter), has been shown to normalize blood pressure and provide protection to mTAL against oxidative injury, respectively. Human HO-1 gene transfer into endothelial cells has been shown to attenuate Ang II- TNF- and heme-mediated DNA damage. Furthermore, delivery of human HO-1 into SHR has been shown to enhance somatic body growth and cell proliferation. The ability to transfect human HO gene and to demonstrate its expression may offer a new therapeutic strategy for treating pathological conditions, such as hypertension, trauma and hemorrhage.

Animals↗
PubMed2003

Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation.

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.

Animals↗
PubMed2004

Stable expression of foreign proteins in herbaceous and apple plants using Apple latent spherical virus RNA2 vectors.

Infectious cDNA clones of Apple latent spherical virus (ALSV)-RNA1 (pEALSR1) and -RNA2 (pEALSR2) were constructed using an enhanced 35S promoter. A viral vector was constructed from pEALSR2 by creating artificial protease processing sites by duplicating the Q/G protease cleavage site between 42KP and Vp25. Eight RNA2-derived vectors expressing GFP with varied sizes of duplications around the 42KP/Vp25 junction were constructed and tested for infectivity in Chenopodium quinoa. The results indicated that greater than five aa from the C-terminus of 42KP and N-terminus of Vp25 in duplication are necessary for systemic infection. In infected C. quinoa plants, GFP fluorescence was observed in both inoculated and upper leaves. Serial passages of the viruses derived from the above vectors in C. quinoa showed that the size of duplications affected the stability of the GFP gene. The version of the RNA2-vector (pER2L5R5GFP) with the shortest duplications and its silent mutant version could stably express GFP in leaves even after at least nine serial passages. ALSV-RNA2 vector has a capacity to maintain a DNA insert as long as 1300 bp because Apple chlorotic leaf spot virus movement protein (50KP) gene could be expressed in C. quinoa. Inoculation of a virus derived from pER2L5R5GFP to apple seedlings resulted in the expression of GFP fluorescence in uninoculated upper leaves, indicating that the vector is available for the expression of foreign genes in apple trees.

Blotting, Western↗
PubMed2005

Use of herpes virus amplicon vectors to study brain disorders.

There is an enormous initiative to establish the genetic basis for disorders of brain function. Unfortunately, genetic intervention is not accomplished easily in the nervous system. One strategy is to engineer and deliver to neurons specialized viral vectors that carry a gene (or genes) of interest, thereby exploiting the natural ability of viruses to insert genetic material into cells. When delivered to brain cells, these vectors cause infected cells to increase the expression of the genes of interest. The ability to deliver genes into neurons in vitro and in vivo with herpes simplex virus (HSV) amplicon vectors has made it possible to carry out exactly these sorts of experiments. This technology has the potential to offer new insights into the etiology of a wide variety of neuropsychiatric disorders. We describe the use of HSV amplicon vectors to study Alzheimer disease, drug addiction, and depression, and discuss the considerations that enter into the use of these vectors both in vitro and in vivo. The HSV amplicon virus is a user-friendly vector for the delivery of genes into neurons that has come of age for the study of brain function.

Animals↗
PubMed2004

Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model: effects of the route of immunization.

In our efforts to develop a strong, effective immune response against cervical carcinoma and premalignant disease, we study the use of recombinant Semliki Forest virus (SFV) encoding the oncoproteins E6 and E7 from high-risk human papilloma viruses (HPVs). Optimal immunization conditions are required for immunotherapeutic treatment of cervical cancer as it has been postulated that cervical cancer patients are immune-suppressed and/or immunologically tolerant for HPV. We previously generated an optimized construct encoding a fusion protein of HPV16 E6 and E7 and a translational enhancer (enhE6,7). Immunization of mice with SFV-enhE6,7 was shown to induce cytoxic T cell (CTL) responses and resulted in the eradication of established tumours. We now demonstrate, using HPV16-specific MHC class I tetramers, that high pCTL frequencies can be induced. However, this induction is strongly influenced by the route of immunization applied. Whilst in bulk CTL assays, requiring in vitro restimulation, CTL activity can be observed upon s.c., i.p., i.v. and i.m. immunization, detectable pCTL frequencies, without in vitro restimulation, are only induced upon i.m. and i.v. immunization. The route of immunization also strongly influences the dose of viral vector needed to induce CTLs and tumour therapy. As few as 5x10(4) SFV-enhE6,7, primed and boosted i.v., are needed to eradicate tumours in six out of seven mice treated. Furthermore, exponentially growing tumours of approximately 500 mm3 in size were seen to completely resolve and even tumours as large as 1500 mm3 decreased to one-third of their size. Apart from this potency, SFV vectors can safely be used for the expression of oncoproteins such as E6 and E7, since the viral RNA is not integrated in the host genome. Thus SFV-enhE6,7 meets with the criteria that a vaccine against cervical cancer should be safe and induce a very strong, long-lasting CTL response, strong enough to eradicate existing tumours.

Animals↗
PubMed2006

Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity.

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.

Adenoviridae↗
PubMed2007

Rapid transport of plasmid DNA into the nucleolus via actin depolymerization using the HVJ envelope vector.

BACKGROUND: Although nuclear transport of therapeutic genes is an essential requirement of human gene therapy, factors required for nuclear entry of DNA remain to be elucidated. Non-viral vector systems have led to numerous improvements in the efficiency of delivery of exogenous DNA into cells. However, nuclear transport of plasmid is difficult to achieve. METHODS: We examined nuclear translocation efficiency of Cy3-labeled plasmid DNA (Cy3-pDNA) delivered by the hemagglutinating virus of Japan envelope (HVJ-E) vector, Lipofectamine or microinjection. We also examined the effect of actin depolymerization on nuclear transport of Cy3-pDNA. RESULTS: Cy3-pDNA reached the nucleus, particularly in the nucleolus, in 30 min after fusion-mediated delivery using the HVJ-E vector, while the DNA was retained in the cytoplasm during the observed period after the delivery by cationic liposomes. HVJ-E treatment transiently depolymerized actin filaments, and acceleration of nucleolar entry of microinjected DNA was achieved when treated with either empty HVJ-E or cytochalasin D, an inhibitor of actin depolymerization, prior to microinjection. CONCLUSIONS: These results suggest that plasmid DNA can be transported rapidly from the cytoplasm to the nucleolus when actin filaments are depolymerized. Thus, the HVJ-E vector can accelerate the transport of DNA to the nucleolus by actin depolymerization.

Actins↗
PubMed2002

Absence of PKR attenuates the anti-HSV-1 activity of an adenoviral vector expressing murine IFN-beta.

A study was undertaken to evaluate the efficacy of an adenoviral vector containing the murine interferon-beta (IFN-beta) transgene (Ad:IFN-beta) against herpes simplex virus type 1 (HSV-1) infection in two transduced cell lines. The transduction of the adenoviral vector efficiency, ranging from 2% to 100%, was dependent on the multiplicity of infection (moi) (0.4-50 plaque-forming units [pfu]/cell). Supernatants from cells transduced with the Ad:IFN-beta but not the adenoviral null vector (Ad:Null) contained biologically active IFN-beta (6.6-106 U/ml depending on the moi). Cells transduced with the Ad:IFN-beta displayed up to 25-fold reduction in viral titers compared with cells transduced with the Ad:Null or nontransduced cell controls. The suppression in viral titer correlated with a reduction in viral gene (alpha, beta, and gamma) and protein expression. The expression of IFN beta-responsive genes, including protein kinase R (PKR) and 2',5'-oligoadenylate synthetase (OAS), were significantly elevated in the Ad:IFN-beta-transduced cells by 12-fold and 25-fold, respectively. However, after infection with HSV-1, a transient but significant drop in PKR but not OAS gene expression was observed 10 h postinfection. The absence of PKR but not RNase L significantly attenuated the antiviral efficacy of the transgene. Collectively, these results illustrate the feasibility of employing a viral vector to deliver a potent antiviral gene to targeted cells without any obvious detriment to the vector itself and support an important role for PKR as a mediator of the anti-HSV-1 activity of type I IFN.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Development of a flexible and specific gene delivery system for production of murine tumor models.

To develop models of human cancer we have expressed the avian retroviral receptor, TVA, under a variety of mammalian promoters in transgenic mice, thus rendering mice susceptible to infection with avian leukosis virus-derived gene vectors. TVA-based retroviral gene transfer offers advantages over current murine models of human cancer. A single transgenic mouse line can be used to evaluate multiple genetic lesions, individually and in combination. Furthermore, mutant genes are introduced somatically into animals, as occurs in the majority of naturally occurring tumors. Because the avian viral vectors replicate only in avian cells, the viral receptor in infected transgenic mouse cells remains available for multiple rounds of infection with different ASLV vectors. We discuss the theoretical and practical aspects of using recombinant avian retroviruses with TVA transgenic mice to generate cancer models.

Alpharetrovirus↗
PubMed2005

Local, non-viral IL-12 gene therapy using a water soluble lipopolymer as carrier system combined with systemic paclitaxel for cancer treatment.

Development of improved gene transfer methods is needed for gene therapy to achieve its clinical potential. The use of biocompatible polymeric gene carriers has shown effectiveness in overcoming the current problems associated with viral vectors in safety, immunogenicity and mutagenesis. Previous work has demonstrated that repeated, local, non-viral interleukin-12 (IL-12) gene delivery successfully slows down tumor progression, while improving immunogenicity. Combining IL-12 gene delivery with systemic paclitaxel (PCT) chemotherapy as a treatment for various subcutaneous mouse mammary carcinomas, we used PCT with either a biodegradable polymeric solubilizer, HySolv or Cremophor EL for systemic treatment and injected water soluble lipopolymer (WSLP)/plasmid-encoding IL-12 gene (p2CMVmIL-12) complexes local once every week. The amount of lung metastases being essential for survival as well as subcutaneous tumor volume were compared against untreated controls. We showed inhibition of tumor growth and decreased lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the PCT only treated groups. Compared to Cremophor, HySolv performed better alone or in combination with IL-12. Using polymeric vectors as gene carrier systems in combination with improved systemic therapies provide evidence for the efficacy and feasibility of polymer-based drug delivery systems. Especially local cytokine gene delivery showed augmentation of systemic chemotherapy while reducing the hosts risk for further systemic toxicity.

Animals↗
PubMed1997

Defective adenoassociated viral-mediated transfection of insulin gene by direct injection into liver parenchyma decreases blood glucose of diabetic mice.

The present study assessed the feasibility of transferring the insulin gene into liver cells of diabetic individuals using a defective adenoassociated viral (AAV) vehicle. AAV offers several advantages over other viral vectors, since this vehicle can facilitate transfection in vivo without cell division and without any viral coding sequences (thus minimizing inflammation). The rat insulin gene and lacZ were each packed into a defective AAV vehicle (AAV-INS and AAV-lacZ, respectively). Successful AAV-mediated transfection and expression of lacZ into hepatocytes in primary cell culture were demonstrated by chemiluminescent assay of beta-galactosidase. Similarly, AAV-mediated transfection and expression of the insulin gene into hepatocytes was demonstrated by immunocytochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). After AAV-mediated transfection of the insulin gene into hepatocytes, glucose in the medium was significantly reduced for up to 5 days. After direct injection of AAV-INS into liver parenchyma of diabetic mice, successful transfection was demonstrated by RT-PCR, and blood glucose was significantly decreased for at least 6 days. These studies suggest that the AAV vector may be used to transfer the insulin gene into liver cells in vitro and in vivo.

Animals↗
PubMed2004

Targeting HSV amplicon vectors.

Several techniques have been developed to deliver DNA directly into mammalian cells, spanning in difficulty from simple mixing procedures to complex systems requiring expensive equipment. Viral vectors have proven able to deliver genes into mammalian cells with high efficiency and low toxicity. In particular, herpes simplex virus type-1 (HSV-1) amplicon vectors are well suited for gene transfer studies as they can infect many cell types, both non-dividing and dividing, have a large transgene capacity and are easy to manipulate. For some applications, it may be desirable to target gene delivery to specific cell populations or to transduce normally non-susceptible cells. This can be achieved by modifying one or more of the glycoproteins found in the viral envelope. Glycoprotein C (gC) has a well-characterized heparan sulfate binding domain (HSBD) necessary for HSV binding to cells. Replacing this region with unique ligands can result in less efficient binding to natural target cells and increase binding to cells which express receptors for these ligands. A method to retarget amplicon vectors by replacing gC HSBD with a model ligand, the hexameric histidine-tag, is described, as well as means to evaluate the binding of modified vector as compared to wild-type virus to cells with or without the appropriate receptor, in this case, a his-tag pseudo-receptor. This protocol demonstrates increased binding of modified virus to receptor-positive cells (at levels greater than wild-type) with no loss of infectivity. Retargeted vectors can provide an additional tool for increasing the efficiency of gene delivery to specific cell types.

Animals↗
PubMed2002

Genetic engineering of meniscal allografts.

Allograft meniscal transplantation represents one of the few available treatment options after menisectomy. Despite acceptable early results, a considerable controversy exists with regard to poor graft regeneration, shrinkage and biomechanical failure of transplanted menisci. Transfer of specific growth factor genes may improve the regeneration process of meniscal allografts. The aim of this study was to investigate the feasibility of gene transfer in meniscal allografts in rabbits. Four different viral vectors encoding marker genes, including lacZ, luciferase, and green fluorescence protein were used to investigate viral transduction in 50 lapine menisci for 4 weeks in vitro. Subsequently, 16 unilateral meniscus replacements were performed with ex vivo retrovirally transduced meniscal allografts, and the expression of the lacZ gene was examined histologically at 2, 4, 6, and 8 weeks after transplantation. Gene expression in the superficial cell layers of the menisci can be detected for up to 4 weeks in vitro, but the level of gene transfer declined over time. The transduction with retrovirus showed better persistence and deep penetration of the menisci with infected cells. In vivo, declining numbers of beta-galactosidase-positive cells were also detected in retrovirally transduced allografts up to 8 weeks. Consistently, transduced cells were found at the menisco-synovial junction of the transplants and in deeper layers of the menisci. There was no evidence of cellular immune response in the transduced transplants. This investigation showed a prospective for growth factor delivery in auto- and allografts. In further experiments, vectors expressing therapeutic proteins such as growth factors will be investigated to assess their potential to improve remodeling and healing of meniscal allografts.

Animals↗
PubMed2004

Utilization of an HSV-based amplicon vector encoding the axonal marker hPLAP to follow neurite outgrowth in cultured DRG neurons.

Delivery of genes into DRG neurons by viral vectors is a powerful tool for the study of axonal outgrowth. In order to achieve efficient transfer of growth-related genes and simultaneously label neuronal processes, we have utilized the HSV-based amplicon vector system. A bicistronic expression cassette encoding the growth associated protein-43 (GAP-43) and the axonal marker human placental alkaline phosphatase (hPLAP) reporter gene under translation control of an internal ribosomal entry site was cloned into the HGCX amplicon vector. This hPLAP reporter enabled efficient labeling of neurites in both dissociated adult DRG neurons and embryonic DRG explants. Using this reporter, the effect of GAP-43 on neurite outgrowth in transduced DRG neurons could be demonstrated. HSV-based amplicon vectors can contribute to the study of axonal growth and guidance in cultured neurons.

Alkaline Phosphatase↗
PubMed2000

Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model.

During the last few years, recombinant viral vectors derived from adenovirus (Ad), adeno-associated virus (AAV) or lentivirus (LV) have been developed into highly effective vehicles for gene transfer to the adult central nervous system. In recent experiments, in the rat model of Parkinson's disease, all three vector systems have been shown to be effective for long-term delivery of glial cell line-derived neurotrophic factor (GDNF) at biologically relevant levels in the nigrostriatal system. Injection of the GDNF encoding vectors into either striatum or substantia nigra thus makes it possible to obtain a regionally restricted over-expression of GDNF within the nigrostriatal system that is sufficient to block the toxin-induced degeneration of the nigral dopamine neurons. Injection of GDNF vectors in the striatum, in particular, is effective not only in rescuing the cell bodies in the substantia nigra, but also in preserving the nigrostriatal projection and a functional striatal dopamine innervation in the rat Parkinson model. Long-term experiments using AAV-GDNF and LV-GDNF vectors show, moreover, that sustained GDNF delivery over 3-6 months can promote regeneration and significant functional recovery in both 6-OHDA-lesioned rats and MPTP-lesioned monkeys. The impressive efficacy of the novel AAV and LV vectors in rodent and primate Parkinson models suggests that the time may now be ripe to explore these vector systems as tools for neuroprotective treatments in patients with Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗