scholarly journals Receptor-ligand supplementation via a self-cleaving 2A peptide–based gene therapy promotes CNS axonal transport with functional recovery

2021 ◽  
Vol 7 (14) ◽  
pp. eabd2590
Author(s):  
Tasneem Z. Khatib ◽  
Andrew Osborne ◽  
Sujeong Yang ◽  
Zara Ali ◽  
Wanyi Jia ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Axonal Transport ◽  
Single Gene ◽  
Gene Replacement ◽  
Receptor Expression ◽  
Neuronal Function ◽  
Down Regulation ◽  
2A Peptide ◽  
Gene Therapy Vector ◽  
Experimental Glaucoma

Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.

Distribution and expression of transgene green fluorescent protein in mice survived up to four weeks following in utero gene therapys

2007 ◽  
Vol 30 (4) ◽  
pp. 98
Author(s):  
P T Yang ◽  
L Huang ◽  
W W Jia ◽  
E D Skarsgard ◽  
C Sy
Keyword(s):  
Gene Therapy ◽  
Green Fluorescent Protein ◽  
Fluorescent Protein ◽  
Single Gene ◽  
Expression Patterns ◽  
Gene Replacement ◽  
In Utero ◽  
Tissue Specific ◽  
Monogenic Disorders ◽  
Green Fluorescent

Gene replacement offers a potential cure for degenerative disorders caused by a single gene deletion or mutation. Diagnoses of monogenic disorders in the fetus enable prenatal gene replacement which may be beneficial from the perspectives of host inflammatory/immune response, efficacy and disease prevention. Purpose: To evaluate the distribution and expression of reporter gene green fluorescent protein (GFP) in the tissues of mice survived up to one month following in utero gene therapy. Methods: Vesicular Stomatitis Virus-G (VSV-G) pseudotyped lentiviral (LV) vector containing GFP was prepared via triple plasmid co-transfection. Time-mated CD-1 mice underwent individual amniotic sac injection with either 1x106 LV particles or saline (controls) on gestational day 16 (term=21d), and were allowed to undergo spontaneous parturition. Pups were sacrificed on postnatal days 0, 7, 21 and 28, and neonatal and maternal tissues were analyzed for GFP transgene (by DNA polymerase chain reaction; PCR), and transgene expression by quantitative reverse transcriptase (QRT) PCR and immunohistochemistry (IHC). Results: We observed selective transduction of neonatal tissues (trachea, lung, liver, heart, kidney, spleen, intestine, skeletal muscle), in pups undergoing in utero transfection with LV-GFP. Maternal tissues did not contain transgene despite exposure during amniotic injection. Although the numbers of pups analyzed at each postnatal time point was small, we observed variable persistence of GFP expression that appeared to be tissue specific (with persistent expression noted in intestine of 4 week old pups). Conclusions: Neonatal tissue transfection occurs in a variety of tissues following amniotic injection with LV-GFP in this murine model of in utero gene therapy. Transgene persistence and expression patterns observed over the first 4 weeks of life may reflect tissue-specific genomic insertion of transgene that favors persistent transcription in select tissues.

Vitamin D decreasesin vitroglucocorticoid sensitivity via down regulation of glucocorticoid receptor expression

2015 ◽  
Author(s):  
Narjes Nasiri Ansari ◽  
Eliana Spilioti ◽  
Vasiliki Kalotychou ◽  
Geena Dalagiorgou ◽  
Paraskevi Moutsatsou ◽  
...  
Keyword(s):  
Vitamin D ◽  
Glucocorticoid Receptor ◽  
Receptor Expression ◽  
Down Regulation

Emerging approaches for restoration of hearing and vision

2020 ◽  
Author(s):  
Sonja Kleinlogel ◽  
Christian Vogl ◽  
Marcus Jeschke ◽  
Jakob Neef ◽  
Tobias Moser
Keyword(s):  
Gene Therapy ◽  
Hearing Aids ◽  
Sensory Information ◽  
Gene Replacement ◽  
Therapeutic Approaches ◽  
Optogenetic Stimulation ◽  
Cellular Specificity ◽  
Socioeconomic Burden ◽  
Comprehensive Reference

Impairments of vision and hearing are highly prevalent conditions limiting the quality of life and presenting a major socioeconomic burden. For long, retinal and cochlear disorders have remained intractable for causal therapies, with sensory rehabilitation limited to glasses, hearing aids, and electrical cochlear or retinal implants. Recently, the application of gene therapy and optogenetics to eye and ear has generated hope for a fundamental improvement of vision and hearing restoration. To date, one gene therapy for the restoration of vision has been approved and undergoing clinical trials will broaden its application including gene replacement, genome editing, and regenerative approaches. Moreover, optogenetics, i.e. controlling the activity of cells by light, offers a more general alternative strategy. Over little more than a decade, optogenetic approaches have been developed and applied to better understand the function of biological systems, while protein engineers have identified and designed new opsin variants with desired physiological features. Considering potential clinical applications of optogenetics, the spotlight is on the sensory systems. Multiple efforts have been undertaken to restore lost or hampered function in eye and ear. Optogenetic stimulation promises to overcome fundamental shortcomings of electrical stimulation, namely poor spatial resolution and cellular specificity, and accordingly to deliver more detailed sensory information. This review aims at providing a comprehensive reference on current gene therapeutic and optogenetic research relevant to the restoration of hearing and vision. We will introduce gene-therapeutic approaches and discuss the biotechnological and optoelectronic aspects of optogenetic hearing and vision restoration.

scholarly journals Immunotherapy and Gene Therapy for Oncoviruses Infections: A Review

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 822
Author(s):  
Nathália Alves Araújo de Almeida ◽  
Camilla Rodrigues de Almeida Ribeiro ◽  
Jéssica Vasques Raposo ◽  
Vanessa Salete de Paula
Keyword(s):  
Gene Therapy ◽  
Checkpoint Inhibitors ◽  
Gene Replacement ◽  
Gene Products ◽  
Transcription Activator ◽  
Therapeutic Gene ◽  
T Lymphotropic Virus ◽  
Barr Virus ◽  
B Virus ◽  
Epstein Barr

Immunotherapy has been shown to be highly effective in some types of cancer caused by viruses. Gene therapy involves insertion or modification of a therapeutic gene, to correct for inappropriate gene products that cause/may cause diseases. Both these types of therapy have been used as alternative ways to avoid cancers caused by oncoviruses. In this review, we summarize recent studies on immunotherapy and gene therapy including the topics of oncolytic immunotherapy, immune checkpoint inhibitors, gene replacement, antisense oligonucleotides, RNA interference, clustered regularly interspaced short palindromic repeats Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based gene editing, transcription activator-like effector nucleases (TALENs) and custom treatment for Epstein–Barr virus, human T-lymphotropic virus 1, hepatitis B virus, human papillomavirus, hepatitis C virus, herpesvirus associated with Kaposi’s sarcoma, Merkel cell polyomavirus, and cytomegalovirus.

scholarly journals RNA Editing as a Therapeutic Approach for Retinal Gene Therapy Requiring Long Coding Sequences

2020 ◽  
Vol 21 (3) ◽  
pp. 777 ◽  
Author(s):  
Lewis E. Fry ◽  
Caroline F. Peddle ◽  
Alun R. Barnard ◽  
Michelle E. McClements ◽  
Robert E. MacLaren
Keyword(s):  
Gene Therapy ◽  
Rna Editing ◽  
Therapeutic Approach ◽  
Genetic Diseases ◽  
Point Mutations ◽  
Transcript Level ◽  
Gene Replacement ◽  
Promising Therapeutic Approach ◽  
Pairing Site ◽  
Large Genes

RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.

scholarly journals Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Sara E. Ratican ◽  
Andrew Osborne ◽  
Keith R. Martin
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Optic Nerve ◽  
Genome Editing ◽  
Optic Neuropathy ◽  
Single Gene ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Potential Use ◽  
Hereditary Optic Neuropathy

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber’s congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber’s hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.

scholarly journals Efficient and Selective Gene Transfer into Primary Human Brain Tumors by Using Single-Chain Antibody-Targeted Adenoviral Vectors with Native Tropism Abolished

2002 ◽  
Vol 76 (6) ◽  
pp. 2753-2762 ◽  
Author(s):  
Victor W. van Beusechem ◽  
Jacques Grill ◽  
D. C. Jeroen Mastenbroek ◽  
Thomas J. Wickham ◽  
Peter W. Roelvink ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Brain Tumors ◽  
Human Brain ◽  
Cancer Gene Therapy ◽  
Adenoviral Vectors ◽  
Receptor Expression ◽  
Normal Brain ◽  
Cancer Gene ◽  
Single Chain

ABSTRACT The application of adenoviral vectors in cancer gene therapy is hampered by low receptor expression on tumor cells and high receptor expression on normal epithelial cells. Targeting adenoviral vectors toward tumor cells may improve cancer gene therapy procedures by providing augmented tumor transduction and decreased toxicity to normal tissues. Targeting requires both the complete abolition of native tropism and the addition of a new specific binding ligand onto the viral capsid. Here we accomplished this by using doubly ablated adenoviral vectors, lacking coxsackievirus-adenovirus receptor and αv integrin binding capacities, together with bispecific single-chain antibodies targeted toward human epidermal growth factor receptor (EGFR) or the epithelial cell adhesion molecule. These vectors efficiently and selectively targeted both alternative receptors on the surface of human cancer cells. Targeted doubly ablated adenoviral vectors were also very efficient and specific with primary human tumor specimens. With primary glioma cell cultures, EGFR targeting augmented the median gene transfer efficiency of doubly ablated adenoviral vectors 123-fold. Moreover, EGFR-targeted doubly ablated vectors were selective for human brain tumors versus the surrounding normal brain tissue. They transduced organotypic glioma and meningioma spheroids with efficiencies similar to those of native adenoviral vectors, while exhibiting greater-than-10-fold-reduced background levels on normal brain explants from the same patients. As a result, EGFR-targeted doubly ablated adenoviral vectors had a 5- to 38-fold-improved tumor-to-normal brain targeting index compared to native vectors. Hence, single-chain targeted doubly ablated adenoviral vectors are promising tools for cancer gene therapy. They should provide an improved therapeutic index with efficient tumor transduction and effective protection of normal tissue.

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