Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders

Shahryari, Ali; Jazi, Marie Saghaeian; Mohammadi, Saeed; Nikoo, Hadi Razavi; Nazari, Zahra; Hosseini, Elaheh; Burtscher, Ingo; Mowla, Seyed Javad; Lickert, Heiko

doi:10.3389/fgene.2019.00868

Cited by 215 publications

(167 citation statements)

References 201 publications

(248 reference statements)

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“…Such vehicles are classified as viral and non-viral gene delivery vectors [21,22]. Viruses are so far the most efficient gene delivery vectors, having reached in some cases clinical approval by the U.S. Food and Drug Administration (FDA) and the market [23]. However, the use of viruses is hampered by their marked immunogenicity, limited carrying capacity, and insertional mutagenesis.…”

Section: Gene Deliverymentioning

confidence: 99%

Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles

Bellucci

Volonterio

2020

Antibiotics

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Aminoglycosides are a class of naturally occurring and semi synthetic antibiotics that have been used for a long time in fighting bacterial infections. Due to acquired antibiotic resistance and inherent toxicity, aminoglycosides have experienced a decrease in interest over time. However, in the last decade, we are seeing a renaissance of aminoglycosides thanks to a better understanding of their chemistry and mode of action, which had led to new trends of application. The purpose of this comprehensive review is to highlight one of these new fields of application: the use of aminoglycosides as building blocks for the development of liposomal and polymeric vectors for gene delivery. The design, synthetic strategies, ability to condensate the genetic material, the efficiency in transfection, and cytotoxicity as well as when available, the antibacterial activity of aminoglycoside-based cationic lipids and polymers are covered and critically analyzed.

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Section: Gene Deliverymentioning

confidence: 99%

Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles

Bellucci

Volonterio

2020

Antibiotics

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“…Briefly, gene therapy can be achieved through the use of advanced viral vectors (e.g., lentiviral, adeno-associated, adenoviral, retroviral [80][81][82][83][84][85]) or non-viral vector systems (e.g., liposomes systems) [86] that drive the therapeutic gene to the host cells [87][88][89][90][91]. The safety and efficacy of these strategies may be evaluated in engineered stem cell models, that are suitable for the treatment validation and for the screening of potential mutational insertions caused by the integration of the target gene in the host DNA [92][93][94][95].…”

Section: Ex Vivo Stem Cell-based Modeling Systemsmentioning

confidence: 99%

Harnessing the Potential of Stem Cells for Disease Modeling: Progress and Promises

Argentati

Tortorella

Bazzucchi

et al. 2020

JPM

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Ex vivo cell/tissue-based models are an essential step in the workflow of pathophysiology studies, assay development, disease modeling, drug discovery, and development of personalized therapeutic strategies. For these purposes, both scientific and pharmaceutical research have adopted ex vivo stem cell models because of their better predictive power. As matter of a fact, the advancing in isolation and in vitro expansion protocols for culturing autologous human stem cells, and the standardization of methods for generating patient-derived induced pluripotent stem cells has made feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Furthermore, the potential of stem cells on generating more complex systems, such as scaffold-cell models, organoids, or organ-on-a-chip, allowed to overcome the limitations of the two-dimensional culture systems as well as to better mimic tissues structures and functions. Finally, the advent of genome-editing/gene therapy technologies had a great impact on the generation of more proficient stem cell-disease models and on establishing an effective therapeutic treatment. In this review, we discuss important breakthroughs of stem cell-based models highlighting current directions, advantages, and limitations and point out the need to combine experimental biology with computational tools able to describe complex biological systems and deliver results or predictions in the context of personalized medicine.Since their establishment, cell cultures have been proven to be the first and most powerful tool for the in vitro investigation of cell biology, from basic research to more complex translational approaches [6]. Classical two-dimensional (2D)-cultures usually consist of a unique type of cells (primary or continuous cultures) that grow in tissue culture polystyrene as adherent monolayers or in floating suspension, both in culture media that provide essential nutrients and growth factors. 2D-strategies are widely used to obtain a large number of cells, thus allowing the in vitro study of molecular mechanisms and development of metabolic assays [7-9]. However, due to their inability to recreate the in vivo complexity of the biological environment, they are not suitable for accurate disease modeling. These limitations have been overcome by the development of three-dimensional (3D)-cell cultures systems [10]. The rationale design of 3D-cell cultures is to harvest cells in microstructures that resemble tissues or organs shape and organization, thus allowing better cell-to-cell/cell-environment contacts and signaling crosstalk [11][12][13][14][15], essential events for tissues correct development and functioning [14,15]. The 3D-cell culture strategy is articulated in many different methods and techniques that can be grouped in scaffold-based or non-scaffold based platforms, each with particular advantages and disadvantages that make them useful for different applications [10,[16][17][18][19]. 3D-cell culture strategies are supported by the in silico...

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“…Pacjenci byli karmieni drogą doustną oraz nie wymagali sztucznej wentylacji. W badaniu STR1VE pojedyncza infuzja dożylna onasemnogene abeparvovec w dawce 1,1 × 10 14 vg/kg mc pozwoliła na szybką poprawę funkcji ruchowych [25]. Zgodnie z danymi z 8 marca 2019 r. -95% z 20 pacjentów, którzy osiągnęli 10,5 miesiąca oraz 87% z 15 pacjentów, którzy osiągnęli 13,6 miesiąca przeżyło bez mechanicznego wspomagania wentylacji.…”

Section: Badania Kliniczneunclassified

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

Majchrzak‐Celińska¹,

Warych²,

Szoszkiewicz³

2020

Farm Pol.

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Farmacja Polska, ISSN 0014-8261 (print); ISSN 2544-8552 (on-line) Spinal muscular atrophy -onasemnogene abeparvovec and other therapeutic optionsSpinal muscular atrophy (SMA) is a neuromuscular disorder that results in the loss of motor neurons. SMA is caused by mutations in the SMN1 gene, leading to the decreased synthesis of the SMN protein, necessary for motor neuron survival. In the past, SMA was considered to be an incurable disease, and therapy was limited only to symptomatic treatment. However, currently there are drugs which effectively inhibit the development of the disease, and even give hope for its cure. Their mechanism of action involves either delivering of a functional copy of the SMN1 gene, or modification of the alternative splicing of the SMN2 gene. Moreover, amelioration of muscle growth and increasing muscle contractility serves as a way of relieving the symptoms of the disease. The functional copy of SMN1 gene is delivered by onasemnogene abeparvovec (Zolgensma). The drug contains cDNA sequences, which correspond to the missing SMN1 gene. It is administered in the form of adeno-associated viral vector serotype 9 (AAV9)-based gene therapy, as a single intravenous infusion, to treat children less than 2 years old. Currently, the drug is approved only in the USA, and its cost exceeds PLN 2,000,000. SMN2 has nearly identical sequence as SMN1, however due to alternative splicing, only around 10% of its transcript results in a full-length, functional SMN protein.Modification of the alternative splicing of the SMN2 pre-mRNA by the drug nusinersen (Spinraza) results in an increased level of the SMN protein. Nusinersen is administered as intrathecal injections and is available both in the USA as well as in Europe. Also risdiplam and branaplam -small-molecule drugs with similar mechanism of action are now being tested in clinical trials. The inhibition of proMyostatin cleavage and slowing calcium release, leads to the increased muscle growth and contractility, respectively. So far, three promising drugs are being evaluated in clinical trials: SRK-015, which is a selective and local inhibitor of the activation of myostatin, as well as reldesemtiv (CK-2127107) and tirasemtiv (CK-2127107), both being the fast skeletal muscle troponin activators. These drugs do not affect the genetic cause of SMA, but relieve the symptoms of the disease. Early diagnosis and treatment gives hope for halting the progress of SMA, preserving motor function and extending patient's life.To jest artykuł o otwartym dostępie, na licencji CC BY NC https://creativecommons.org/licenses/by-nc/4.0/

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Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders

Cited by 215 publications

References 201 publications

Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles

Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles

Harnessing the Potential of Stem Cells for Disease Modeling: Progress and Promises

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

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