New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

Daga, Sergio; Donati, Francesco; Capitani, Katia; Croci, Susanna; Tita, Rossella; Giliberti, Annarita; Valentino, Floriana; Benetti, Elisa; Fallerini, Chiara; Niccheri, Francesca; Baldassarri, Margherita; Mencarelli, Maria Antonietta; Frullanti, Elisa; Furini, Simone; Conticello, Silvestro G.; Renieri, Alessandra; Pinto, Anna Maria

doi:10.1038/s41431-019-0537-8

Cited by 33 publications

(27 citation statements)

References 30 publications

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“…This should prompt the reevaluation of living-donor kidney transplantation guidelines in various genetic kidney diseases [211]. Furthermore, the pathogenicity of splicing variants could be easily confirmed at the transcript level in primary podocytes derived from urine of Alport syndrome patients with intronic variants in COL4A3, COL4A4 or COL4A5 genes [139].…”

Section: Utility Of Urine-derived Epithelial Cells As Models For Genetic Kidney Diseasesmentioning

confidence: 99%

Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

Bondue

Arcolino

Veys

et al. 2021

Cells

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Epithelial cells exfoliated in human urine can include cells anywhere from the urinary tract and kidneys; however, podocytes and proximal tubular epithelial cells (PTECs) are by far the most relevant cell types for the study of genetic kidney diseases. When maintained in vitro, they have been proven extremely valuable for discovering disease mechanisms and for the development of new therapies. Furthermore, cultured patient cells can individually represent their human sources and their specific variants for personalized medicine studies, which are recently gaining much interest. In this review, we summarize the methodology for establishing human podocyte and PTEC cell lines from urine and highlight their importance as kidney disease cell models. We explore the well-established and recent techniques of cell isolation, quantification, immortalization and characterization, and we describe their current and future applications.

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Section: Utility Of Urine-derived Epithelial Cells As Models For Genetic Kidney Diseasesmentioning

confidence: 99%

Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

Bondue

Arcolino

Veys

et al. 2021

Cells

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“…A 2019 study reported the successful use of CRISPR-Cas9 gene editing in cultured urine-derived podocytes from patients with Alport syndrome. 174 This approach achieved homologous correction in 59% of variant in COL4A5 (Gly624Asp) and 44% of variants in COL4A3 (Gly856Glu) 174 . Exon skipping therapy [G] can also be induced by CRISPR-Cas9, or with splice-blocking antisense oligonucleotides.…”

Section: [H1] Therapy For Gbm-associated Diseasementioning

confidence: 99%

Complexities of the glomerular basement membrane

2020

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The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. Major components of the GBM include laminins, collagen IV, nidogens and heparan sulphate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5 and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic disease such as diabetes mellitus. Current treatment for diseases associated with GBM involvement aims to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease.

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“…Sergio Daga (Medical Genetics, University of Siena, Siena, Italy), from the group of Aelssandra Renieri, has employed a two-plasmid CRISPR/Cas9 genome editing approach, achieving a beneficial and stable correction of the COL4 loss-of-function variants on urine-derived podocyte-lineage cells (Fig. 3B ) [ 55 , 56 ]. In order to translate the in-vitro application into a future in-vivo clinical trial, dogs and mice have been used as preclinical animal models to investigate the safety and efficacy of the system.…”

Section: Gene Therapy Approaches Using Gene Editingmentioning

confidence: 99%

The 2019 and 2021 International Workshops on Alport Syndrome

et al. 2022

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In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: COL4A3 , COL4A4 , and COL4A5 encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome.

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New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

Cited by 33 publications

References 30 publications

Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

Complexities of the glomerular basement membrane

The 2019 and 2021 International Workshops on Alport Syndrome

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