Artificial miRNAs are potential gene therapy tools, especially for incurable monogenic disorders

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Brain Surgery ◽  
Native Protein ◽  
Intravenous Injections ◽  
Monogenic Disorders ◽  
Monogenic Diseases ◽  
Short Hairpin ◽  
The Cost ◽  
Short Hairpin Rnas

Well-designed artificial miRNAs (amiRNAs) are as effective as short hairpin RNAs (shRNAs) but produce 10–80 times less siRNA. They enable long-term silencing and are safer than other RNAi triggers. They are suitable instruments for gene therapy techniques, especially for incurable monogenic diseases. In clinical studies, stereotactic injection of AAV5 directly into the striatum is the most effective approach. Intravenous injections would not only make patients more comfortable, but would also reduce the cost of complex brain surgery. In terms of structure, biogenesis, and expression levels, Ami RNAs are more "natural" than other gene therapy methods. They also utilise the cell's native protein machinery and do not produce irreversible alterations, unlike genome editing technologies. The amount of time spent on a technology determines its level of progression. ASOs have an edge in this regard, as seen by the number of authorized medicines. Perhaps RNAi is just around the corner.

scholarly journals Gene therapy with hematopoietic stem and progenitor cell for monogenic disorders: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Francesca Tucci ◽  
Stefania Galimberti ◽  
Luigi Naldini ◽  
Maria G Valsecchi ◽  
Alessandro Aiuti
Keyword(s):  
Gene Therapy ◽  
Metabolic Diseases ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Primary Immunodeficiencies ◽  
Hematopoietic Stem ◽  
Monogenic Disorders ◽  
Monogenic Diseases ◽  
Stem And Progenitor Cells ◽  
Ex Vivo Gene Therapy

Abstract To provide an assessment of the safety of ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPC), we reviewed in a systematic manner the literature on monogenic diseases to describe survival, genotoxicity and engraftment of gene corrected HSPC, across vector platforms and diseases. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death was 0.9 per 100 person-years of observation (PYO) (95%CI = 0.37–2.17). There were 21 genotoxic events out of 1504.02 PYO. All these events occurred in γRV trials (0.99 events per 100 PYO, 95%CI = 0.18–5.43) for primary immunodeficiencies. Pooled rate of engraftment was 86.1% (95%CI = 66.9–95.0%) for γRV and 99.0% (95%CI = 95.1–99.8%) for LV HSPC-GT (p = 0.002). A comprehensive meta-analysis on HSPC-GT showed stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPC.

Peptide Shuttle-Mediated Delivery for Brain Gene Therapies

2020 ◽  
Vol 20 (32) ◽  
pp. 2945-2958
Author(s):  
Josep Garcia ◽  
Pol Arranz-Gibert ◽  
Macarena Sánchez-Navarro ◽  
Ernest Giralt ◽  
Meritxell Teixidó
Keyword(s):  
Gene Therapy ◽  
Special Focus ◽  
Gene Therapies ◽  
Efficient Gene ◽  
Wide Range ◽  
Monogenic Diseases ◽  
Delivery Strategies ◽  
Inpatient Safety ◽  
Broad Overview

The manipulation of an individual’s genetic information to treat a disease has revolutionized the biomedicine field. Despite the promise of gene therapy, this treatment can have long-term sideeffects. Efforts in the field and recent discoveries have already led to several improvements, including efficient gene delivery and transfer, as well as inpatient safety. Several studies to treat a wide range of pathologies-such as cancer or monogenic diseases- are currently being conducted. Here we provide a broad overview of methodologies available for gene therapy, placing a strong emphasis on treatments for central nervous system diseases. Finally, we give a perspective on current delivery strategies to treat such diseases, with a special focus on systems that use peptides as delivery vectors.

Gene therapy for the treatment of spinal muscular atrophy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Gene Targeting ◽  
Muscular Atrophy ◽  
Target Engagement ◽  
Delivery Method ◽  
The Us ◽  
Or Gene ◽  
The Cost

The FDA has now approved three innovative gene targeting treatments for the treatment of individuals with spinal muscular atrophy (SMA), each with its own unique delivery method. The need for therapy optimization is underlined by the variety in clinical outcomes, notwithstanding this remarkable success. More basic and translational research is needed to determine the factors that limit cell and tissue medication biodistribution and target engagement, as well as to assess long-term durability and potential toxicities. This research in SMA will be crucial in the development of successful gene-targeting therapeutics for other neurogenetic illnesses. The expensive expense of SMA therapies has received a lot of media attention. Nusinersen costs $125,000 each dose, with numerous treatments costing more than $1 million; while risdiplam is scheduled to be price-capped at up to $340,000 each year (91, 92). The cost of gene-targeting drugs is unsustainable, especially because the US Food and Drug Administration anticipates approving 10 to 20 cell or gene therapy products each year by 2025. Efforts must be taken to address these rising costs in order for all patients to benefit from precision medicine.

scholarly journals Considerations for Preclinical Safety Assessment of Adeno-Associated Virus Gene Therapy Products

2018 ◽  
Vol 46 (8) ◽  
pp. 1020-1027 ◽  
Author(s):  
Basel T. Assaf ◽  
Laurence O. Whiteley
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Metabolic Diseases ◽  
Adeno Associated Virus ◽  
Monogenic Disorders ◽  
Iatrogenic Complications ◽  
Health And Disease ◽  
Molecular Bases ◽  
Preclinical Safety

Progress in understanding the molecular bases of human health and disease in recent decades has flourished making it possible for the field of gene therapy (GT) to offer new possibilities for treating, and even curing, a plethora of medical conditions such as monogenic disorders and metabolic diseases. GT is a therapeutic intervention to genetically alter or modify living cells by means of gene delivery achieved using either viral vectors or nonviral vectors, with adeno-associated virus (AAV) vectors constituting market-share majority. Although GT is conceptually attractive, adverse and even fatal iatrogenic complications have marred the initial enthusiasm of clinical successes. The properties of investigational AAV-based GT may pose safety concerns unique from those of small molecule drugs and other macromolecular biologics, such as ectopic or unregulated expression of the transgene, long-term persistence, and off-target distribution. Herein, we discuss considerations in the design of a comprehensive preclinical safety program for AAV-based GT prior to administration in humans.

scholarly journals Gene knockdown via electroporation of short hairpin RNAs in embryos of the marine hydroid Hydractinia symbiolongicarpus

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gonzalo Quiroga-Artigas ◽  
Alexandrea Duscher ◽  
Katelyn Lundquist ◽  
Justin Waletich ◽  
Christine E. Schnitzler
Keyword(s):  
Gene Function ◽  
Marine Invertebrates ◽  
Endogenous Gene ◽  
Successful Model ◽  
Hydractinia Symbiolongicarpus ◽  
Endogenous Genes ◽  
Short Hairpin ◽  
Visual Confirmation ◽  
Short Hairpin Rnas

Abstract Analyzing gene function in a broad range of research organisms is crucial for understanding the biological functions of genes and their evolution. Recent studies have shown that short hairpin RNAs (shRNAs) can induce gene-specific knockdowns in two cnidarian species. We have developed a detailed, straightforward, and scalable method to deliver shRNAs into fertilized eggs of the hydrozoan cnidarian Hydractinia symbiolongicarpus via electroporation, yielding effective gene-targeted knockdowns that can last throughout embryogenesis. Our electroporation protocol allows for the transfection of shRNAs into hundreds of fertilized H. symbiolongicarpus eggs simultaneously with minimal embryo death and no long-term harmful consequences on the developing animals. We show RT-qPCR and detailed phenotypic evidence of our method successfully inducing effective knockdowns of an exogenous gene (eGFP) and an endogenous gene (Nanos2), as well as knockdown confirmation by RT-qPCR of two other endogenous genes. We also provide visual confirmation of successful shRNA transfection inside embryos through electroporation. Our detailed protocol for electroporation of shRNAs in H. symbiolongicarpus embryos constitutes an important experimental resource for the hydrozoan community while also serving as a successful model for the development of similar methods for interrogating gene function in other marine invertebrates.

scholarly journals Retroviral gene therapy in Germany with a view on previous experience and future perspectives

Gene Therapy ◽  
2021 ◽  
Author(s):  
Michael A. Morgan ◽  
Melanie Galla ◽  
Manuel Grez ◽  
Boris Fehse ◽  
Axel Schambach
Keyword(s):  
Gene Therapy ◽  
Cell Function ◽  
Immune Cell ◽  
Retroviral Vectors ◽  
Hematopoietic Stem ◽  
Gene Therapy Vector ◽  
Cell Therapies ◽  
Gene Therapies ◽  
Monogenic Disorders ◽  
Monogenic Diseases

AbstractGene therapy can be used to restore cell function in monogenic disorders or to endow cells with new capabilities, such as improved killing of cancer cells, expression of suicide genes for controlled elimination of cell populations, or protection against chemotherapy or viral infection. While gene therapies were originally most often used to treat monogenic diseases and to improve hematopoietic stem cell transplantation outcome, the advent of genetically modified immune cell therapies, such as chimeric antigen receptor modified T cells, has contributed to the increased numbers of patients treated with gene and cell therapies. The advancement of gene therapy with integrating retroviral vectors continues to depend upon world-wide efforts. As the topic of this special issue is “Spotlight on Germany,” the goal of this review is to provide an overview of contributions to this field made by German clinical and research institutions. Research groups in Germany made, and continue to make, important contributions to the development of gene therapy, including design of vectors and transduction protocols for improved cell modification, methods to assess gene therapy vector efficacy and safety (e.g., clonal imbalance, insertion sites), as well as in the design and conduction of clinical gene therapy trials.

Primary varicose veins

Phlebologie ◽  
2010 ◽  
Vol 39 (03) ◽  
pp. 133-137
Author(s):  
H. Partsch
Keyword(s):  
Varicose Veins ◽  
Compression Therapy ◽  
Daily Practice ◽  
Clinical Severity ◽  
Compression Stockings ◽  
Primary Varicose Veins ◽  
The Cost ◽  
Convincing Data ◽  
Long Term Studies

SummaryBackground: Compression stockings are widely used in patients with varicose veins. Methods: Based on published literature three main points are discussed: 1. the rationale of compression therapy in primary varicose veins, 2. the prescription of compression stockings in daily practice, 3. studies required in the future. Results: The main objective of prescribing compression stockings for patients with varicose veins is to improve subjective leg complaints and to prevent swelling after sitting and standing. No convincing data are available concerning prevention of progression or of complications. In daily practice varicose veins are the most common indication to prescribe compression stockings. The compliance depends on the severity of the disorder and is rather poor in less severe stages. Long-term studies are needed to proof the cost-effectiveness of compression stockings concerning subjective symptoms and objective signs of varicose veins adjusted to their clinical severity. Conclusion: Compression stockings in primary varicose veins are able to improve leg complaints and to prevent swelling.

An Evaluation of Provincial Macroeconomic Performance in Vietnam

2017 ◽  
pp. 34-47
Author(s):  
Hoi Le Quoc ◽  
Nam Pham Xuan ◽  
Tuan Nguyen Anh
Keyword(s):  
Development Strategy ◽  
Institutional Transformation ◽  
Economic Indicators ◽  
Macroeconomic Performance ◽  
Economic Development Strategy ◽  
Socio Economic Development ◽  
The Cost ◽  
Development Objectives ◽  
First Time

The study was targeted at developing a methodology for constructing a macroeconomic performance index at a provincial level for the first time in Vietnam based on 4 groups of measurements: (i) Economic indicators; (ii) oriented economic indicators; (iii) socio-economic indicators; and (iv) economic - social – institutional indicators. Applying the methodology to the 2011 - 2015 empirical data of all provinces in Vietnam, the research shows that the socio-economic development strategy implemented by those provinces did not provide balanced outcomes between growth and social objectives, sustainability and inclusiveness. Many provinces focused on economic growth at the cost of structural change, equality and institutional transformation. In contrast, many provinces were successful in improving equality but not growth. Those facts threaten the long-term development objectives of the provinces.

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