Nieuwe moleculaire mechanismen en therapeutische opties voor renaal Fanconi syndroom: Een focus op cystinose
Year: 2024
Type: dissertation
Abstract: Cystinosis is an autosomal recessive lysosomal storage disorder. It is caused by a mutation in the CTNS-gene, which encodes the lysosomal transporter protein cystinosin. Cystinosin is a cystine-proton symporter that transports cystine out of the lysosome. Hence, in patients with cystinosis, cystinosin deficiency causes cystine accumulation in the lysosomes and results in several manifestations all over the body. The kidneys are the first and most severly affected, with the generalized proximal tubular dysfunction (called renal Fanconi syndrome) as the first to appear. The diagnosis of cystinosis is currently based on the detection of elevated cystine in polymorphonuclear white blood cells by high-performance liquid chromatography or liquid chromatography and tandem mass spectrometry, often followed by a genetic analysis of the CTNS gene. The current standard therapy for cystinosis is aminothiol cysteamine, which reduces the disulphide bond of cystine to form cysteine and the cysteine-cysteamine mixed disulphide complex. These molecules can be transported out of the lysosomes by their own transporters. Cysteamine is not a curative therapy, but only delays the progression of renal and extra-renal disease manifestations. Cysteamine also has several side effects and therefore, the search for new therapies in cystinosis is ongoing. First, I suggested methods of improvement for the diagnosis of cystinosis, by showing that the genetic analysis of the CTNS gene should be placed center-stage and that future diagnostic strategies may include the measurement of cystine levels in slow-dividing cells if there are discrepancies between the phenotype of the patient, the CTNS variant, and the white blood cell cystine measurement. This will allow for a more rapid and accurate diagnosis, and an earlier therapeutic intervention. Furthermore, I presented two potential new therapeutic approaches that could be used for cystinosis. On one hand, the mRNA-based protein replacement was able to reduce cystine levels for a prolonged period of time, resulted in a restoration of the proximal tubular dysfunction and ameliorated the proteinuria in a cystinosis zebrafish model. Importantly, the mRNA-therapy can be easily extended to treat other genetic (kidney) diseases by using different mRNAs. However, to apply this approach in the clinical setting, the development of appropriate delivery vehicles is of paramount importance and will decide tissue distribution. On the other hand, I showed that the depletion of MFSD12 (a transporter that is responsible for the lysosomal import of cysteine and thereby a contributer to the cystine accumulation) could be used to reduce cystine levels, but was not able to result in any improvement of the proximal tubular function.
Source: Lirias (KU Leuven)
Author: Bondue, Tjessa
Institution: KU Leuven
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Verbundprojekt: Translationale Forschung zur Verbesserung von Diagnostik und Therapie der FSGS TP2, G3054257492, G6898640633, Study of kidney progenitor cells and potential of gene therapy in nephropathic cystinosis., Investigating the potential of CTNS-mRNA loaded nanoparticles as a new therapeutic strategy for nephropathic cystinosis., G8137446682, Investigating the potential of CTNS-mRNA loaded nanoparticles as a new therapeutic strategy for nephropathic cystinosis
OpenAlex ID: W7030589015
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