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Lysosomal, sterol and lipid disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This disorder is caused by impaired transport of the amino acid cystine. Proteins are composed of a number of different amino acids, one of which is cystine. These proteins are broken down into amino acids in a specialised part of the cell called the lysosome, so that they can be reused by the body. Once the breakdown has occurred, cystine is normally transported out of the lysosome. In cystinosis, there is a problem with transporting the cystine out of the lysosome, which results in a build-up of cystine in this part of the cell. Because of its structure, cystine crystallises in all tissues, but the kidneys and the eyes are particularly afected.
Carbon Black Tinted Contact Lenses for Reduction of Photophobia in Cystinosis Patients
Published in Current Eye Research, 2019
Cystinosis is an autosomal recessive disorder that affects 1 in 100,000–200,000 people in the general population1 that stems from a defect in the CTNS gene, which was mapped to the chromosome. A total of 17,9132,3 CTNS is responsible for the production of cystinosin, a transport protein found in the lysosomal membranes.4 Under normal function, proteins are transported into the lysosomes to be broken down into amino acids, where they can be reused for additional biological processes.5 Cystinosin is responsible for the transport of the specific amino acid cystine across the membrane. Cystine is the oxidized dimer of cysteine, both of which are crucial for normal cell function.6–8
Ex vivo gene therapy for lysosomal storage disorders: future perspectives
Published in Expert Opinion on Biological Therapy, 2023
Edina Poletto, Andrew Oliveira Silva, Ricardo Weinlich, Priscila Keiko Matsumoto Martin, Davi Coe Torres, Roberto Giugliani, Guilherme Baldo
Ex vivo gene therapy has come a long way since its original conception to nowadays modern techniques. The same statement can be applied to the knowledge involving diagnosis, pathogenic mechanisms, and treatments for lysosomal disorders. Diseases where the traditional HSCT was believed to be ineffective, such as MPS II, have recently shown that, if performed early, can lead to important clinical benefits. The same can be said for other disorders, such as cystinosis. These discoveries have increased the number of diseases where an ex vivo gene therapy approach has the potential to be effective, and the field has grown tremendously in the last years, with several clinical trials already being conducted.
ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease
Published in Expert Opinion on Investigational Drugs, 2020
Cystinosis is an ultra-rare autosomal recessive lysosomal storage disorder caused by mutations in the cystinosin gene (CTNS) which encodes the cystinosin lysosomal transporter [13,14]. When left untreated, cystinosis is characterized by the pediatric onset of progressive renal insufficiency requiring dialysis or kidney transplantation by 10–12 years of age [14]. Approximately 12% of cases of cystinosis are caused by nonsense mutations [15]. Cystinosin is ubiquitously expressed and functions as a cystine-proton co-transporter, an activity required to remove cystine released from protein degradation in the lysosome [13]. Defects in cystinosin may lead to cystine accumulation and the formation of intra-lysosomal crystals. The tissues impacted, severity and age of onset are dependent upon the patient’s CTNS genotype [16]. Mutations that result in a loss of cystine transport are associated with severe infantile presentation of the disease. Identification of mutations that inhibit transport activity can also be observed in individuals with later, juvenile onset disease suggesting that there may be additional cystinosin functions outside of cystine transport which contribute to some aspects of the disease [16]. Cystine accumulation within lysosomes can be reduced through cysteamine-mediated conversion of cystine to cysteine, which can then be removed from the lysosome [17]. The approval of cysteamine in the early 1990s and subsequent approval of extended release formulations has provided a therapeutic option for individuals with the disease. Early treatment with cysteamine bitartrate depletes intra-lysosomal cystine, helps manage the disease, and improves the outcome of cystinosis complications; however, it does not halt disease progression or kidney manifestations [18,19].