Improving Molecular Therapy in the Kidney

Rubin, Jeffrey D.; Barry, Michael A.

doi:10.1007/s40291-020-00467-6

Cited by 25 publications

(28 citation statements)

References 183 publications

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“…This filtration takes place in the glomerulus (specifically in the glomerular filtration membrane-GFM) of each nephron [166]. Blood, via the afferent arteriole, reaches the glomerulus, where molecules with a weight greater than 50 kDa and a size greater than 10 nm are excluded [166][167][168]. Blood is drained from the glomerulus through the efferent arteriole that branches forming the peritubular capillaries (PTCs), which extend along the PT and DCT, producing the exchange of substances.…”

Section: Difficulty Of Gene Delivery To the Kidneymentioning

confidence: 99%

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Gómez-García

Martínez-Pulleiro

Carrera

et al. 2022

Cells

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Genetic kidney diseases (GKDs) are a group of rare diseases, affecting approximately about 60 to 80 per 100,000 individuals, for which there is currently no treatment that can cure them (in many cases). GKDs usually leads to early-onset chronic kidney disease, which results in patients having to undergo dialysis or kidney transplant. Here, we briefly describe genetic causes and phenotypic effects of six GKDs representative of different ranges of prevalence and renal involvement (ciliopathy, glomerulopathy, and tubulopathy). One of the shared characteristics of GKDs is that most of them are monogenic. This characteristic makes it possible to use site-specific nuclease systems to edit the genes that cause GKDs and generate in vitro and in vivo models that reflect the genetic abnormalities of GKDs. We describe and compare these site-specific nuclease systems (zinc finger nucleases (ZFNs), transcription activator-like effect nucleases (TALENs) and regularly clustered short palindromic repeat-associated protein (CRISPR-Cas9)) and review how these systems have allowed the generation of cellular and animal GKDs models and how they have contributed to shed light on many still unknown fields in GKDs. We also indicate the main obstacles limiting the application of these systems in a more efficient way. The information provided here will be useful to gain an accurate understanding of the technological advances in the field of genome editing for GKDs, as well as to serve as a guide for the selection of both the genome editing tool and the gene delivery method most suitable for the successful development of GKDs models.

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Section: Difficulty Of Gene Delivery To the Kidneymentioning

confidence: 99%

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Gómez-García

Martínez-Pulleiro

Carrera

et al. 2022

Cells

View full text Add to dashboard Cite

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“…Based on the anatomical structure of the kidneys, local delivery to the different compartments can be achieved with high efficiency using several routes [ 116 , 117 ] ( Figure 1 and Table 1 ): (1) renal artery, targeting the glomeruli and tubular epithelium. Podocytes within the glomerulus create slit diaphragms with diameters of only 10 nm.…”

Section: Overcoming Delivery Problemsmentioning

confidence: 99%

“…Similar to what occurs in the renal artery, increased localized pressure in the renal capillaries creates transient pores on cell membranes, resulting in nucleic acid extravasation [ 18 , 22 , 61 ]; (3) retrograde ureteral administration, targeting the tubular epithelium; (4) intraparenchymal administration. Some reports have already demonstrated the suitability of using this route for the treatment of renal diseases by using gene therapy [ 116 , 119 ] and oligonucleotides delivered by viral vectors [ 30 , 32 , 33 ] ( Table 1 ).…”

Section: Overcoming Delivery Problemsmentioning

confidence: 99%

“…Similarly, the use of replication-deficient shRNA expression adenovirus vectors have also demonstrated promising results targeting the kidney, as shown by a recent study [ 33 ]. Nevertheless, comparable to what occurs with lentiviral vector development, their high immunogenicity severely limits their potential for clinical purposes [ 116 ]. Another alternative includes the use of AAV, whose absence of human pathogenicity make them attractive candidates.…”

Section: Overcoming Delivery Problemsmentioning

confidence: 99%

“…Indeed, a study carried out by Wang et al [ 28 ] delivered an AAV carrying an shRNA targeting the mineralocorticoid receptor of the kidney in rats, achieving efficient silencing. Contrary to adenovirus or lentivirus, AAV present a smaller size and genetic-carrying capacity (25 nm/4,7 kb vs. 100 nm/36 kb and 130 nm/9kb respectively) [ 116 ]. However, this should not be an issue when packaging short oligonucleotide precursors.…”

Section: Overcoming Delivery Problemsmentioning

confidence: 99%

See 2 more Smart Citations

Oligonucleotide-Based Therapies for Renal Diseases

et al. 2021

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The global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging as novel and promising alternatives to traditional drugs. Their expansion corresponds with new knowledge regarding the molecular basis underlying CKD, and they are already showing encouraging preclinical results, with two candidates being evaluated in clinical trials. However, despite recent technological advances, efficient kidney delivery remains challenging, and the presence of off-targets and side-effects precludes development and translation to the clinic. In this review, we provide an overview of the various oligotherapeutic strategies used preclinically, emphasizing the most recent findings in the field, together with the different strategies employed to achieve proper kidney delivery. The use of different nanotechnological platforms, including nanocarriers, nanoparticles, viral vectors or aptamers, and their potential for the development of more specific and effective treatments is also outlined.

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Gene therapy for pediatric genetic kidney diseases

Song

Sun

et al. 2023

Pediatric Discovery

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Genetic kidney disease is the main cause of chronic kidney disease in children. While the pathogenic genes associated with most genetic kidney diseases have been identified, the underlying mechanisms of disease initiation remain ambiguous, and effective treatment modalities are limited. Gene therapy has emerged as a promising approach for treating genetic diseases. Several gene therapy drugs have been successfully launched to treat genetic diseases affecting the eyes and muscles. However, the development of gene therapy agents for kidney diseases lags behind that of other genetic disorders. In this review, we first comprehensively summarize the main gene therapy strategies. Next, we provide an overview of current treatment options as well as the latest research on gene therapy approaches for pediatric genetic kidney diseases with a particular emphasis on Alport syndrome and polycystic kidney disease. Finally, we discuss the challenges and potential solutions for gene therapy of pediatric genetic kidney diseases.

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Improving Molecular Therapy in the Kidney

Cited by 25 publications

References 183 publications

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Oligonucleotide-Based Therapies for Renal Diseases

Gene therapy for pediatric genetic kidney diseases

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