scholarly journals Muscle-Specific Promoters for Gene Therapy

Acta Naturae ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 47-58
Author(s):  
Victoria V. Skopenkova ◽  
Tatiana V. Egorova ◽  
Maryana V. Bardina
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Genetic Diseases ◽  
Gene Replacement ◽  
Regulatory Sequences ◽  
Muscle Creatine Kinase ◽  
Specific Expression ◽  
Drug Candidates ◽  
Muscular Disorders ◽  
Preclinical Trials

Many genetic diseases that are responsible for muscular disorders have been described to date. Gene replacement therapy is a state-of-the-art strategy used to treat such diseases. In this approach, the functional copy of a gene is delivered to the affected tissues using viral vectors. There is an urgent need for the design of short, regulatory sequences that would drive a high and robust expression of a therapeutic transgene in skeletal muscles, the diaphragm, and the heart, while exhibiting limited activity in non-target tissues. This review focuses on the development and improvement of muscle-specific promoters based on skeletal muscle -actin, muscle creatine kinase, and desmin genes, as well as other genes expressed in muscles. The current approaches used to engineer synthetic muscle-specific promoters are described. Other elements of the viral vectors that contribute to tissue-specific expression are also discussed. A special feature of this review is the presence of up-to-date information on the clinical and preclinical trials of gene therapy drug candidates that utilize muscle-specific promoters.

Non-Viral Vectors for Gene Delivery

2018 ◽  
Vol 9 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Aparna Bansal ◽  
Himanshu
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Transfection Efficiency ◽  
Gene Transfection ◽  
Expression System ◽  
Target Cells ◽  
Specific Expression ◽  
Naked Dna

Introduction: Gene therapy has emerged out as a promising therapeutic pave for the treatment of genetic and acquired diseases. Gene transfection into target cells using naked DNA is a simple and safe approach which has been further improved by combining vectors or gene carriers. Both viral and non-viral approaches have achieved a milestone to establish this technique, but non-viral approaches have attained a significant attention because of their favourable properties like less immunotoxicity and biosafety, easy to produce with versatile surface modifications, etc. Literature is rich in evidences which revealed that undoubtedly, non–viral vectors have acquired a unique place in gene therapy but still there are number of challenges which are to be overcome to increase their effectiveness and prove them ideal gene vectors. Conclusion: To date, tissue specific expression, long lasting gene expression system, enhanced gene transfection efficiency has been achieved with improvement in delivery methods using non-viral vectors. This review mainly summarizes the various physical and chemical methods for gene transfer in vitro and in vivo.

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 Gene therapy for hearing loss

2019 ◽  
Vol 28 (R1) ◽  
pp. R65-R79 ◽  
Author(s):  
Ryotaro Omichi ◽  
Seiji B Shibata ◽  
Cynthia C Morton ◽  
Richard J H Smith
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Inner Ear ◽  
Viral Vectors ◽  
Therapeutic Potential ◽  
Late Onset ◽  
Science Research ◽  
Gene Replacement ◽  
Age Related ◽  
Genetic And Environmental Factors

Abstract Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.

scholarly journals TREATMENT POSSIBILITIES FOR ACQUIRED AND HEREDITARY DISEASES BY GENE THERAPY: A REVIEW

2021 ◽  
pp. 26-32
Author(s):  
P. V. KAMALA KUMARI ◽  
G. EKSHITHA, V. HARIKA
Keyword(s):  
Gene Therapy ◽  
Nucleic Acids ◽  
Viral Vectors ◽  
Target Gene ◽  
Genetic Diseases ◽  
Hereditary Diseases ◽  
Root Cause ◽  
Delivery Strategies ◽  
Foreign Genes ◽  
And Control

Therapeutic nucleic acids demand specificity and accuracy in design as well as delivery strategies used in replacement or silencing of the target gene. Gene therapy is believed to be the therapy in which the root cause of the diseases can be treated at the molecular level. Generally gene therapy helps in the identification of the origin of the disorder instead of using drugs to diminish or control the symptoms. The application of nucleic acids to treat and control diseases is known as “gene therapy.” Gene therapy consists on the substitution or addition of a functional gene into the nucleus of a living cell, in order to treat a disease or repair a dysfunction, caused by this gene failure. This therapy is used to correct defective genes, which are responsible for genetic diseases. Thus, gene therapy can be used to prevent, treat or regulate hereditary or acquired disorders, by the production of therapeutic proteins. The gene therapy is mediated by the use of viral and non-viral vectors to transport foreign genes into somatic cells to restorative defective genes. This review focuses on viral vectors in detail.

Specific transgene expression in human and mouse CD4+cells using lentiviral vectors with regulatory sequences from theCD4 gene

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3416-3423 ◽  
Author(s):  
Gilles Marodon ◽  
Enguerran Mouly ◽  
Emma J. Blair ◽  
Charlotte Frisen ◽  
François M. Lemoine ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Cd4 T Cells ◽  
Transgene Expression ◽  
Lentiviral Vectors ◽  
Egfp Expression ◽  
Regulatory Sequences ◽  
Cd4 Cells ◽  
Specific Expression ◽  
Hematopoietic Stem

Achieving cell-specific expression of a therapeutic transgene by gene transfer vectors represents a major goal for gene therapy. To achieve specific expression of a transgene in CD4+ cells, we have generated lentiviral vectors expressing the enhanced green fluorescent protein (eGFP) reporter gene under the control of regulatory sequences derived from theCD4 gene—a minimal promoter and the proximal enhancer, with or without the silencer. Both lentiviral vectors could be produced at high titers (more than 107 infectious particles per milliliter) and were used to transduce healthy murine hematopoietic stem cells (HSCs). On reconstitution of RAG-2–deficient mice with transduced HSCs, the specific vectors were efficiently expressed in T cells, minimally expressed in B cells, and not expressed in immature cells of the bone marrow. Addition of the CD4gene-silencing element in the vector regulatory sequences led to further restriction of eGFP expression into CD4+ T cells in reconstituted mice and in ex vivo–transduced human T cells. Non–T CD4+ dendritic and macrophage cells derived from human CD34+ cells in vitro expressed the transgene of the specific vectors, albeit at lower levels than CD4+ T cells. Altogether, we have generated lentiviral vectors that allow specific targeting of transgene expression to CD4+ cells after differentiation of transduced mice HSCs and human mature T cells. Ultimately, these vectors may prove useful for in situ injections for in vivo gene therapy of HIV infection or genetic immunodeficiencies.

scholarly journals Gene Replacement Therapy: A Primer for the Health-system Pharmacist

2019 ◽  
Vol 33 (6) ◽  
pp. 846-855 ◽  
Author(s):  
John Petrich ◽  
Dominic Marchese ◽  
Chris Jenkins ◽  
Michael Storey ◽  
Jill Blind
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Expert Opinion ◽  
Viral Vectors ◽  
Professional Associations ◽  
The United States ◽  
Gene Replacement ◽  
World Health ◽  
Risk Level ◽  
Gene Replacement Therapy

Purpose: Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. Summary: There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. Conclusion: Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.

scholarly journals Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

2021 ◽  
Vol 14 ◽  
Author(s):  
Thomas Leth Jensen ◽  
Casper René Gøtzsche ◽  
David P. D. Woldbye
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Muscular Atrophy ◽  
Ex Vivo ◽  
Genetic Diseases ◽  
Gene Replacement ◽  
Gene Therapies ◽  
Rare Genetic Diseases ◽  
Brain And Spinal Cord ◽  
The Brain

In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.

scholarly journals Innovative therapies in genetic diseases: Cystic fibrosis

2021 ◽  
Vol 70 (1) ◽  
pp. 16-20
Author(s):  
Elena-Silvia Shelby ◽  
◽  
Florina Mihaela Nedelea ◽  
Tanser Huseyinoglu ◽  
Relu Cocos ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Antisense Oligonucleotides ◽  
Viral Vectors ◽  
Genetic Diseases ◽  
Wild Type ◽  
Gene Encoding ◽  
Innovative Therapies ◽  
Type Gene

Cystic fibrosis, also named mucoviscidosis, is the most frequent hereditary pulmonary disease and is produced by mutations in the CFTR gene, encoding an anionic channel for chloride and bicarbonate involved in the regulation of salt and bicarbonate metabolisms. Currently, about half of the patients with cystic fibrosis can benefit personalized therapy consisting in modulators, drugs which restore or improve the functionality and stability of CFTR. Moreover, presently, other therapies, such as gene therapy using the CRISP/CAS-9, modified antisense oligonucleotides or the insertion of the wild-type gene using nanolipidic particles or viral vectors, are being developed. This article aims to take stock of the principal types of cystic fibrosis therapies which have been approved or are in clinical trials.

Local and global gene therapy in the central nervous system

1995 ◽  
Vol 18 (1) ◽  
pp. 76-78
Author(s):  
Leslie L. Muldoon ◽  
Edward A. Neuwelt
Keyword(s):  
Gene Therapy ◽  
Transgene Expression ◽  
Viral Vectors ◽  
Gene Replacement ◽  
Transient Nature ◽  
Gene Replacement Therapy ◽  
The Central Nervous System ◽  
Localized Delivery ◽  
Altered Cell ◽  
Genetic Vectors

AbstractFor focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable.

scholarly journals Prospects for the Use of Artificial Chromosomes and Minichromosome-Like Episomes in Gene Therapy

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sara Pérez-Luz ◽  
Javier Díaz-Nido
Keyword(s):  
Gene Therapy ◽  
Genetic Diseases ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Regulatory Sequences ◽  
Mitotic Chromosomes ◽  
Physiological Regulation ◽  
Artificial Chromosomes ◽  
Recessive Mutations ◽  
Dividing Cells

Artificial chromosomes and minichromosome-like episomes are large DNA molecules capable of containing whole genomic loci, and be maintained as nonintegrating, replicating molecules in proliferating human somatic cells. Authentic human artificial chromosomes are very difficult to engineer because of the difficulties associated with centromere structure, so they are not widely used for gene-therapy applications. However, OriP/EBNA1-based episomes, which they lack true centromeres, can be maintained stably in dividing cells as they bind to mitotic chromosomes and segregate into daughter cells. These episomes are more easily engineered than true human artificial chromosomes and can carry entire genes along with all their regulatory sequences. Thus, these constructs may facilitate the long-term persistence and physiological regulation of the expression of therapeutic genes, which is crucial for some gene therapy applications. In particular, they are promising vectors for gene therapy in inherited diseases that are caused by recessive mutations, for example haemophilia A and Friedreich's ataxia. Interestingly, the episome carrying the frataxin gene (deficient in Friedreich's ataxia) has been demonstrated to rescue the susceptibility to oxidative stress which is typical of fibroblasts from Friedreich's ataxia patients. This provides evidence of their potential to treat genetic diseases linked to recessive mutations through gene therapy.

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