Tissue and cell-type-specific transduction using rAAV vectors in lung diseases

Kochergin-Nikitsky, Konstantin S.; Belova, Lyubava; Лавров, А. В.; Smirnikhina, Svetlana

doi:10.1007/s00109-021-02086-y

Cited by 10 publications

(5 citation statements)

References 150 publications

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“…In our work, we assessed the efficiency of transduction of rAAV2/6, rAAV2/9, and rAdV5 and transfection using the Neon Transfection System into hiBCs. The serotypes of the viral vectors have a tropism for lung epithelial cells (Lenman, 2016;Kochergin-Nikitsky et al, 2021). By comparing the maximum efficacy values in each group, we demonstrated that among rAAV vectors, rAAV2/6 is more effective for hiBC transduction (94.7% ± 0.9% at 2E+06 MOI) than rAAV2/9 (87.1% ± 3.5% at 5E+06 MOI, p < 0.0332).…”

Section: Discussionmentioning

confidence: 89%

Airway basal cells from human-induced pluripotent stem cells: a new frontier in cystic fibrosis research

Demchenko,

Belova,

Balyasin

et al. 2024

Front. Cell Dev. Biol.

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Human-induced airway basal cells (hiBCs) derived from human-induced pluripotent stem cells (hiPSCs) offer a promising cell model for studying lung diseases, regenerative medicine, and developing new gene therapy methods. We analyzed existing differentiation protocols and proposed our own protocol for obtaining hiBCs, which involves step-by-step differentiation of hiPSCs into definitive endoderm, anterior foregut endoderm, NKX2.1+ lung progenitors, and cultivation on basal cell medium with subsequent cell sorting using the surface marker CD271 (NGFR). We derived hiBCs from two healthy cell lines and three cell lines with cystic fibrosis (CF). The obtained hiBCs, expressing basal cell markers (NGFR, KRT5, and TP63), could differentiate into lung organoids (LOs). We demonstrated that LOs derived from hiBCs can assess cystic fibrosis transmembrane conductance regulator (CFTR) channel function using the forskolin-induced swelling (FIS) assay. We also carried out non-viral (electroporation) and viral (recombinant adeno-associated virus (rAAV)) serotypes 6 and 9 and recombinant adenovirus (rAdV) serotype 5 transgene delivery to hiBCs and showed that rAAV serotype 6 is most effective against hiBCs, potentially applicable for gene therapy research.

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Section: Discussionmentioning

confidence: 89%

Airway basal cells from human-induced pluripotent stem cells: a new frontier in cystic fibrosis research

Demchenko,

Belova,

Balyasin

et al. 2024

Front. Cell Dev. Biol.

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“…To date, many trials using RNA-based and DNA-based therapeutics have been done or are in progress. The use of recombinant adeno-associated virus (rAAV) as a vector seems to be the most explored method of delivery [50][51][52][53], but other nanodelivery tools, such as lipid nanoparticle encapsulating Cas9 mRNA and sgRNA, are also under investigation [54][55][56].…”

Section: Potential Strategies For Atp12a Targetingmentioning

confidence: 99%

ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases

Dębczyński,

Gorrieri,

Mojsak

et al. 2023

Biomolecules

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ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties of the fluid and mucus lining the respiratory epithelia, which are essential to maintain the airway host defense and the respiratory health. Increased expression and activity of ATP12A in combination with the loss of other balancing activities, such as the bicarbonate secretion mediated by CFTR, leads to excessive acidification of the airway surface liquid and mucus dysfunction, processes that play relevant roles in the pathogenesis of cystic fibrosis and other chronic inflammatory respiratory disorders. In this review, we summarize the findings dealing with ATP12A expression, function, and modulation in the airways, which led to the consideration of ATP12A as a potential therapeutic target for the treatment of cystic fibrosis and other airway diseases; we also highlight the current advances and gaps regarding the development of therapeutic strategies aimed at ATP12A inhibition.

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“…To date, various methods have been developed for creating mutant vectors based on natural AAV serotypes. [54,112,113] For example, modification of capsids by targeted introduction of amino acid substitutions, as well as oligopeptide inserts into the capsid proteins of natural AAV serotypes makes it possible to modulate tissue specificity and thereby exhibit high specificity for various target cell types. In addition to modifying AAV by inserting oligopeptides into the capsid, specific ligands can be added to the surface receptors of target cells.…”

Section: Cellular Heterogeneity Of Organoidsmentioning

confidence: 99%

“…This can be achieved by synthesizing the second strand with the host cell DNA polymerase or by annealing of the plus and minus strands. After the synthesis of the complementary DNA strand, transcription and translation from open reading frames occur (the figure is reproduced from [ 54 ] with modifications)…”

Section: Introductionmentioning

confidence: 99%

“…The use of AAV as a vector for the delivery of therapeutic genes is limited by the vector's low packaging capacity, which does not allow the delivery of large genes (more than 4.5 kb), [ 54 ] so only three drugs have been approved for gene therapy. However, there are a large number of diseases associated with abnormalities of small genes [ 82 ] ; there exist approaches that allow the delivery of truncated genes, [ 83 ] as well as new developments in the field of delivery of large genes in rAAV‐based split systems [ 84 ] All this significantly expands the list of disorders for which the rAAV vectors will be a suitable delivery vehicle.…”

Section: Introductionmentioning

confidence: 99%

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Organoid transduction using recombinant adeno‐associated viral vectors: Challenges and opportunities

2022

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Cellular 3D structures, for example, organoids, are an excellent model for studying and developing treatments for various diseases, including hereditary ones. Therefore, they are increasingly being used in biomedical research. From the point of view of safety and efficacy, recombinant adeno-associated viral (rAAV) vectors are currently most in demand for the delivery of various transgenes for gene replacement therapy or other applications. The delivery of transgenes using rAAV vectors to various types of organoids is an urgent task, however, it is associated with a number of problems that are discussed in this review. Cellular heterogeneity and specifics of cultivation of 3D structures determine the complexity of rAAV delivery and are sometimes associated with low transduction efficiency. This review surveys the main ways to solve emerging problems and increase the efficiency of transgene delivery using rAAVs to organoids. A clear understanding of the stage of development of the organoid, its cellular composition and the presence of surface receptors will allow obtaining high levels of organoid transduction with existing rAAV vectors.

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Tissue and cell-type-specific transduction using rAAV vectors in lung diseases

Cited by 10 publications

References 150 publications

Airway basal cells from human-induced pluripotent stem cells: a new frontier in cystic fibrosis research

Airway basal cells from human-induced pluripotent stem cells: a new frontier in cystic fibrosis research

ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases

Organoid transduction using recombinant adeno‐associated viral vectors: Challenges and opportunities

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