Gene therapy for neurodegenerative and ocular diseases using lentiviral vectors

2005 ◽  
Vol 110 (1) ◽  
pp. 37-46 ◽  
Author(s):  
G. Scott Ralph ◽  
Katie Binley ◽  
Liang-Fong Wong ◽  
Mimoun Azzouz ◽  
Nicholas D. Mazarakis
Keyword(s):  
Gene Therapy ◽  
Nervous System ◽  
Viral Vectors ◽  
Viral Vector ◽  
Lentiviral Vectors ◽  
Great Promise ◽  
Ocular Diseases ◽  
Vector Systems ◽  
Gene Therapy Application ◽  
Wide Range

Gene therapy holds great promise for the treatment of a wide range of inherited and acquired disorders. The development of viral vector systems to mediate safe and long-lasting expression of therapeutic transgenes in specific target cell populations is continually advancing. Gene therapy for the nervous system is particularly challenging due to the post-mitotic nature of neuronal cells and the restricted accessibility of the brain itself. Viral vectors based on lentiviruses provide particularly attractive vehicles for delivery of therapeutic genes to treat neurological and ocular diseases, since they efficiently transduce non-dividing cells and mediate sustained transgene expression. Furthermore, novel routes of vector delivery to the nervous system have recently been elucidated and these have increased further the scope of lentiviruses for gene therapy application. Several studies have demonstrated convincing therapeutic efficacy of lentiviral-based gene therapies in animal models of severe neurological disorders and the push for progressing such vectors to the clinic is ongoing. This review describes the key features of lentiviral vectors that make them such useful tools for gene therapy to the nervous system and outlines the major breakthroughs in the potential use of such vectors for treating neurodegenerative and ocular diseases.

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Gene Therapy Approaches

2021 ◽  
Vol 1 (1) ◽  
pp. 52-56
Author(s):  
Hogir Saadi
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Nuclear Translocation ◽  
Viral Vector ◽  
Ex Vivo ◽  
Genetic Material ◽  
Target Tissue ◽  
Human Beings ◽  
Vector Systems

Gene therapy can be described broadly as the transfer of genetic material to control a disease or at least to enhance a patient's clinical status. The transformation of viruses into genetic shuttles is one of the core principles of gene therapy, which will introduce the gene of interest into the target tissue and cells. To do this, safe strategies have been invented, using many viral and non-viral vector delivery. Two major methods have emerged: modification in vivo and modification ex vivo. For gene therapeutic approaches which are focused on lifelong expression of the therapeutic gene, retrovirus, adenovirus, adeno-associated viruses are acceptable. Non-viral vectors are much less successful than viral vectors, but because of their low immune responses and their broad therapeutic DNA ability, they have advantages. The addition of viral functions such as receptor-mediated uptake and nuclear translocation of DNA may eventually lead to the development of an artificial virus in order to improve the role of non-viral vectors. For human use in genetic conditions, cancers and acquired illnesses, gene transfer techniques have been allowed. The ideal delivery vehicle has not been identified, although the accessible vector systems are capable of transporting genes in vivo into cells. Therefore, only with great caution can the present viral vectors be used in human beings and further progress in the production of vectors is required. Current progresses in our understanding of gene therapy approaches and their delivery technology, as well as the victors used to deliver therapeutic genes, are the primary goals of this review. For that reason, a literature search on PubMed and Google Scholar was carried out using different keywords.

scholarly journals Viral-Vector Delivered anti-Angiogenic Therapies to the Eye

2020 ◽  
Author(s):  
Sanna Koponen ◽  
Emmi Kokki ◽  
Kati Kinnunen ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Gene Therapy ◽  
Clinical Studies ◽  
Viral Vectors ◽  
Vision Loss ◽  
Viral Vector ◽  
Great Promise ◽  
Ocular Neovascularization ◽  
Vessel Growth ◽  
Lentivirus Vectors ◽  
Endothelial Growth Factors

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in pre-clinical studies. Most of the studies has conducted with different adeno-associate serotype vectors. In addition, Adeno and lentivirus vectors have been used. Therapy has targeted to block vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded phase 2 trials further.

scholarly journals Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 219
Author(s):  
Sanna Koponen ◽  
Emmi Kokki ◽  
Kati Kinnunen ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Vision Loss ◽  
Viral Vector ◽  
Great Promise ◽  
Vascular Endothelial ◽  
Ocular Neovascularization ◽  
Vessel Growth ◽  
Lentivirus Vectors ◽  
Endothelial Growth Factors

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in preclinical studies. Most of the studies have been conducted with different adeno-associated serotype vectors. In addition, adeno- and lentivirus vectors have been used. Therapy has been targeted towards blocking vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded further than Phase 2 trials.

Establishing Safety in the Clinic for the First Lentiviral Vector To Be Tested in Humans.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 411-411
Author(s):  
Boro Dropulic ◽  
Laurent Humeau ◽  
Vladimir Slepushkin ◽  
Xiaobin Lu ◽  
Peter Manilla ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Opportunistic Infections ◽  
Lentiviral Vector ◽  
Lentiviral Vectors ◽  
Envelope Gene ◽  
Rev Response Element ◽  
Cd4 Counts ◽  
Viral Loads ◽  
Gene Therapy Application ◽  
Wide Range

Abstract Lentiviral vectors (LV) offer improved therapeutic benefit of gene therapy applications as a result of their ability to stably transduce a wide range of cycling and non-cycling cells. The first Phase I clinical trial using a lentiviral vector, VRX496, was initiated in January of 2003. The vector evaluated is an HIV-1 based lentiviral vector, fully gutted but retaining the 5′ and 3′ long terminal repeats, the packaging sequence, cPPT/CTS, splice donor and splice acceptor, and rev response element (RRE). VRX496 contains a splice-independent 937-base antisense sequence targeting the envelope gene in the HIV genome, and a small 186-base tag derived from the GFP gene to serve as a molecular marker for vector in HIV infected patient cells. Five (5) HIV-infected patients with CD4 counts between 200 and 500, and viral loads above 5000 copies/ml, no history of opportunistic infections, who have failed two regiments of highly active antiretroviral therapy (HAART), were serially enrolled in the trial. After leukopheresis, patient’s CD4 T lymphocytes were isolated by negative selection of CD8+ cells, and then cultured for three days in the presence of immobilized CD3/28 beads, and VRX496. Thereafter, the vector and beads were removed, cells were expanded to the dose of 1 x 1010, and then given intravenously over 15 minutes. At the time of this abstract, 4 patients have been dosed and have passed the initial 21-day safety assessment; a fifth patient is scheduled for dosing. No serious adverse events have occurred. All patients have steady CD4 counts, and viral loads have decreased below baseline in all patients, notably from 218,000 pre dose to 36,000 1 year post dosing in the first patient, and from 22,000 pre dose to 1,625 at 9 months post dosing in the second patient; patients 3 and 4 are at 3 months and 21 days post-infusion, respectively. Importantly, persistence of vector-modified CD4 cells are detected in the peripheral blood out to 9 months post dosing. This trial establishes for the first time the safety of lentiviral vectors for clinical gene therapy application.

scholarly journals VipariNama: RNA viral vectors to rapidly elucidate the relationship between gene expression and phenotype

2021 ◽  
Author(s):  
Arjun Khakhar ◽  
Cecily Wang ◽  
Ryan Swanson ◽  
Sydney Stokke ◽  
Furva Rizvi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Viral Vectors ◽  
Viral Vector ◽  
Tobacco Rattle Virus ◽  
Plant Size ◽  
Great Promise ◽  
Attractive Alternative ◽  
Gibberellin Biosynthesis ◽  
In Planta

Abstract Synthetic transcription factors have great promise as tools to help elucidate relationships between gene expression and phenotype by allowing tunable alterations of gene expression without genomic alterations of the loci being studied. However, the years-long timescales, high cost, and technical skill associated with plant transformation have limited their use. In this work we developed a technology called VipariNama (ViN) in which vectors based on the Tobacco Rattle Virus (TRV) are used to rapidly deploy Cas9-based synthetic transcription factors and reprogram gene expression in planta. We demonstrate that ViN vectors can implement activation or repression of multiple genes systemically and persistently over several weeks in Nicotiana benthamiana, Arabidopsis (Arabidopsis thaliana), and tomato (Solanum lycopersicum). By exploring strategies including RNA scaffolding, viral vector ensembles, and viral engineering, we describe how the flexibility and efficacy of regulation can be improved. We also show how this transcriptional reprogramming can create predictable changes to metabolic phenotypes, such as gibberellin biosynthesis in N. benthamiana and anthocyanin accumulation in Arabidopsis, as well as developmental phenotypes, such as plant size in N. benthamiana, Arabidopsis, and tomato. These results demonstrate how ViN vector-based reprogramming of different aspects of gibberellin signaling can be used to engineer plant size in a range of plant species in a matter of weeks. In summary, VipariNama accelerates the timeline for generating phenotypes from over a year to just a few weeks, providing an attractive alternative to transgenesis for synthetic transcription factor-enabled hypothesis testing and crop engineering.

scholarly journals Pseudotyping Lentiviral Vectors: When the Clothes Make the Virus

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1311 ◽  
Author(s):  
Alexis Duvergé ◽  
Matteo Negroni
Keyword(s):  
Gene Therapy ◽  
Genetic Modification ◽  
Viral Vectors ◽  
Molecular Level ◽  
Lentiviral Vectors ◽  
Human Cells ◽  
Surface Proteins ◽  
Holy Grail ◽  
Viral Therapy

Delivering transgenes to human cells through transduction with viral vectors constitutes one of the most encouraging approaches in gene therapy. Lentivirus-derived vectors are among the most promising vectors for these approaches. When the genetic modification of the cell must be performed in vivo, efficient specific transduction of the cell targets of the therapy in the absence of off-targeting constitutes the Holy Grail of gene therapy. For viral therapy, this is largely determined by the characteristics of the surface proteins carried by the vector. In this regard, an important property of lentiviral vectors is the possibility of being pseudotyped by envelopes of other viruses, widening the panel of proteins with which they can be armed. Here, we discuss how this is achieved at the molecular level and what the properties and the potentialities of the different envelope proteins that can be used for pseudotyping these vectors are.

scholarly journals Layered Double Hydroxide as a Potent Non-viral Vector for Nucleic Acid Delivery Using Gene-Activated Scaffolds for Tissue Regeneration Applications

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1219
Author(s):  
Lara S. Costard ◽  
Domhnall C. Kelly ◽  
Rachael N. Power ◽  
Christopher Hobbs ◽  
Sonia Jaskaniec ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Layered Double Hydroxide ◽  
Viral Vectors ◽  
Viral Vector ◽  
Nucleic Acid Delivery ◽  
Safe Alternative ◽  
Transfection Efficacy ◽  
Mass Ratios ◽  
Low Cytotoxicity ◽  
Double Hydroxide

Nonviral vectors offer a safe alternative to viral vectors for gene therapy applications, albeit typically exhibiting lower transfection efficiencies. As a result, there remains a significant need for the development of a nonviral delivery system with low cytotoxicity and high transfection efficacy as a tool for safe and transient gene delivery. This study assesses MgAl-NO3 layered double hydroxide (LDH) as a nonviral vector to deliver nucleic acids (pDNA, miRNA and siRNA) to mesenchymal stromal cells (MSCs) in 2D culture and using a 3D tissue engineering scaffold approach. Nanoparticles were formulated by complexing LDH with pDNA, microRNA (miRNA) mimics and inhibitors, and siRNA at varying mass ratios of LDH:nucleic acid. In 2D monolayer, pDNA delivery demonstrated significant cytotoxicity issues, and low cellular transfection was deemed to be a result of the poor physicochemical properties of the LDH–pDNA nanoparticles. However, the lower mass ratios required to successfully complex with miRNA and siRNA cargo allowed for efficient delivery to MSCs. Furthermore, incorporation of LDH–miRNA nanoparticles into collagen-nanohydroxyapatite scaffolds resulted in successful overexpression of miRNA in MSCs, demonstrating the development of an efficacious miRNA delivery platform for gene therapy applications in regenerative medicine.

Gene Therapy: Paving New Roads in the Treatment of Hemophilia

2019 ◽  
Vol 45 (07) ◽  
pp. 743-750 ◽  
Author(s):  
Gabriela G. Yamaguti-Hayakawa ◽  
Margareth C. Ozelo
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Pediatric Patients ◽  
Viral Vector ◽  
Monogenic Disease ◽  
Adeno Associated Virus ◽  
Underlying Liver Disease ◽  
Experimental Animal Models ◽  
The Road ◽  
Gene Therapy Application

AbstractHemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field.

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