Below is a selection of cystinosis related research going on around the world. This is not a complete list and will be added to over time. If you have a piece of research you would like us to include here, please contact [email protected].
Cells: Cells runs special issues to create collections of papers on specific topics. The aim is to build a community of authors and readers to discuss the latest research and develop new ideas and research directions. Special Issues are led by Guest Editors who are experts in the subject and oversee the editorial process for papers.
https://doi.org/10.3390/books978-3-0365-4567-7
Editor: Elena N. Levtchenko
Affiliation: Department of Pediatric Nephrology, Development and Regeneration, University Hospitals Leuven, KU Leuven—University of Leuven, Herestraat 49, Box 817, 3000 Leuven, Belgium
Preface
Cystinosis has much to offer as a model disease – multisystem involvement, disease progression, fascinating histopathology, definitive diagnostics, symptomatic and directed therapies involving small molecules and other interventions, unsolved cell biological mysteries, robust clinical and basic research, substantial academic interest and financial support, numerous active advocacy groups, and a rich history of investigations. It is no wonder that a Special Issue of Cells is devoted to this intriguing lysosomal storage disease. It is also most appropriate to dedicate this issue to the father of cystinosis research, Jerry Schneider, MD. Jerry identified the lysosomal location of cystine storage, trained a generation of clinical and basic investigators, fostered the formation of advocacy groups, and formed a community dedicated to the advancement of our understanding and treatment of cystinosis. He would beam with pride to see the articles in this issue elucidating the natural history of muscle, bone, central nervous system, and testicular involvement; model systems and biomarkers to study renal tubular dysfunction; mechanisms of cell death, autophagy, and inflammation; therapeutic benefits of cysteamine; and the potential for gene therapy. Perhaps the most impactful contribution will be the introduction of molecular-based new-born screening for cystinosis, which would bring current and future therapies to cystinosis patients shortly after birth, before significant kidney damage ensues. This is the yield of Jerry’s early work, the harvest of the seed he sowed. William A. Gahl, National Institute of Health, Bethesda, USA.
Abstract
Cystinosis is a rare lysosomal storage disease that is tightly linked with the name of the American physician and scientist Dr. Jerry Schneider. Dr. Schneider (1937–2021) received his medical degree from Northwestern University, followed by a paediatrics residency at Johns Hopkins University and a fellowship in inherited disorders of metabolism. He started to work on cystinosis in J. Seegmiller’s laboratory at the National Institutes of Health (NIH) and subsequently moved to the UC San Diego School of Medicine, where he devoted his entire career to people suffering from this devastating lysosomal storage disorder. In 1967, Dr. Schneider’s seminal Science paper ‘Increased cystine in leukocytes from individuals homozygous and heterozygous for cystinosis’ opened a new era of research towards understanding the pathogenesis and finding treatments for cystinosis patients. His tremendous contribution transformed cystinosis from a fatal disorder of childhood to a treatable chronic disease, with a new generation of cystinosis patients being now in their 40th and 50th years. Dr Schneider wrote a fascinating ‘Personal History of Cystinosis’ highlighting the major milestones of cystinosis research. Unfortunately, he passed away before this manuscript could be published. Fifty-five years after his first paper on cystinosis, the ‘Personal History of Cystinosis’ by Dr Schneider is a tribute to his pioneering discoveries in the field and an inspiration for young doctors and scientists who have taken over the torch of cystinosis research towards finding a cure for cystinosis.
Keywords: cystinosis; lysosomal storage disorder; history; treatment strategies for cystinosis
Received: 21 February 2022/ Accepted: 23 February 2022 Published: 10 March 2022
Scientific Reports
https://doi.org/10.1038/s41598-022-07750-y
Authors: Valeria Graceffa
Affiliation: Cellular Health and Toxicology Research Group (CHAT), Institute of Technology Sligo, Ash Ln, Bellanode, Sligo, Ireland
Centre for Mathematical Modelling and Intelligent Systems for Health and Environment (MISHE), Institute of Technology Sligo, Ash Ln, Bellanode, Sligo, Ireland
Abstract
Cystinosis is a rare disease, caused by a mutation in the gene cystinosin and characterised by the accumulation of cystine crystals. Advantages of biomaterial-mediated gene delivery include reduced safety concerns and the possibility to cure organs that are difficult to treat using systemic gene transfer methods. This study developed novel fibrin hydrogels for controlled, localised gene delivery, for the treatment of cystinosis. In the first part, fabrication parameters (i.e., DNA, thrombin, and aprotinin concentrations) were optimised, using a Design of Experiment (DOE) methodology. DOE is a statistical engineering approach to process optimisation, which increases experimental efficiency, reduces the number of experiments, takes into consideration interactions between different parameters, and allows the creation of predictive models. This study demonstrated the utility of DOE to the development of gene delivery constructs. In the second part of the study, primary fibroblasts from a patient with cystinosis were seeded on the biomaterials. Seeded cells expressed the recombinant CTNS and showed a decrease in cystine content. Furthermore, conditioned media contained functional copies of the recombinant CTNS. These were taken up by monolayer cultures of non-transfected cells. This study described a methodology to develop gene delivery constructs by using a DOE approach and ultimately provided new insights into the treatment of cystinosis.
Received: 08 November 2021/ Accepted 11 February 2022/ Published 08 March 2022
Transition of young adult kidney transplant recipients
Pediatric Nephrology
https://doi.org/10.1007/s00467-022-05582-6
Authors: Mina Matsuda‑Abedini1 · Stephen D. Marks2,3 · Bethany J. Foster4,5,6
Affiliations:
1 Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
2 NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
3 Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
4 Department of Pediatrics, McGill University, Montreal, Canada
5 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
6 Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
Abstract
Survival of pediatric kidney transplant recipients has improved over the past six decades. However, adolescents and young adults still have the highest graft failure rates of any age group. There is a growing need for well-designed transition programs to ensure the successful integration of young adults into adult society with eventual transfer of care and management in adult transplant centers. In this review, we discuss the risk factors contributing to the high risk of kidney graft failure observed between 17 and
24 years of age, including the role of transfer from pediatric to adult care. We also address the unique challenges of adolescents with kidney transplant: the impact of chronic kidney disease on neurocognition, age-related changes in immune activity, and suboptimal adherence during the transition process. We then describe strategies to mitigate these risks by designing developmentally appropriate transition programs, and review the evidence supporting the benefts of well-designed multidisciplinary transition programs.
Keywords: Adolescent, Young adult, Kidney transplantation, Transfer, Transition to adult care
Received: 29 January 2022 / Revised: 3 April 2022 / Accepted: 4 April 2022
© The Author(s), under exclusive licence to International Pediatric Nephrology Association 2022
| Physical and mechanical cues affecting biomaterial-mediated plasmid DNA delivery: insights into non-viral delivery systems
J Genet Eng Biotechnol. 2021 Jun 17;19(1):90. doi: 10.1186/s43141-021-00194-3. Author Valeria Graceffa 1 2 Affiliations
Abstract Background: Whilst traditional strategies to increase transfection efficiency of non-viral systems aimed at modifying the vector or the polyplexes/lipoplexes, biomaterial-mediated gene delivery has recently sparked increased interest. This review aims at discussing biomaterial properties and unravelling underlying mechanisms of action, for biomaterial-mediated gene delivery. DNA internalisation and cytoplasmic transport are initially discussed. DNA immobilisation, encapsulation and surface-mediated gene delivery (SMD), the role of extracellular matrix (ECM) and topographical cues, biomaterial stiffness and mechanical stimulation are finally outlined. Main text: Endocytic pathways and mechanisms to escape the lysosomal network are highly variable. They depend on cell and DNA complex types but can be diverted using appropriate biomaterials. 3D scaffolds are generally fabricated via DNA immobilisation or encapsulation. Degradation rate and interaction with the vector affect temporal patterns of DNA release and transgene expression. In SMD, DNA is instead coated on 2D surfaces. SMD allows the incorporation of topographical cues, which, by inducing cytoskeletal re-arrangements, modulate DNA endocytosis. Incorporation of ECM mimetics allows cell type-specific transfection, whereas in spite of discordances in terms of optimal loading regimens, it is recognised that mechanical loading facilitates gene transfection. Finally, stiffer 2D substrates enhance DNA internalisation, whereas in 3D scaffolds, the role of stiffness is still dubious. Conclusion: Although it is recognised that biomaterials allow the creation of tailored non-viral gene delivery systems, there still are many outstanding questions. A better characterisation of endocytic pathways would allow the diversion of cell adhesion processes and cytoskeletal dynamics, in order to increase cellular transfection. Further research on optimal biomaterial mechanical properties, cell ligand density and loading regimens is limited by the fact that such parameters influence a plethora of other different processes (e.g. cellular adhesion, spreading, migration, infiltration, and proliferation, DNA diffusion and release) which may in turn modulate gene delivery. Only a better understanding of these processes may allow the creation of novel robust engineered systems, potentially opening up a whole new area of biomaterial-guided gene delivery for non-viral systems. Keywords: Biomaterial-mediated gene delivery; Extracellular matrix cues; Mechanical cues; Non-viral gene delivery systems; Surface-mediated gene delivery; Topographic cues. |
| Gold nanoparticle synthesis in contact lenses for drug-less ocular cystinosis treatment
Eur J Pharm Biopharm. 2021 Aug;165:271-278. doi: 10.1016/j.ejpb.2021.05.019. Epub 2021 May 24. Authors Zhen Liu 1 , Uday B Kompella 2 , Anuj Chauhan 3 Affiliations
Abstract Purpose: To develop gold nanoparticles-loaded contact lens (“GoldinLens”) to bind a significant mass of cystine on the surface of the gold nanoparticles (GNPs) for cystinosis treatment due to the reaction between cystine and gold. Methods: The GoldinLens was manufactured by synthesizing GNPs inside the preformed contact lens matrix by first loading the lenses (Moist and TrueEye) with gold precursor followed by reduction (with sodium borohydride or trisodium citrate) to gold atoms, which nucleated to GNPs inside the polymeric matrix. The lenses were characterized by SEM, XRD, UV-Vis spectroscopy and mass of GNPs loaded in the lens was determined by direct measurement of mass. Manufactured lenses were soaked in cystine solution for cystine uptake in vitro. Results: Results show that gold loading in the contact lens increases linearly with gold precursor concentration and number of repetitions of the manufacturing process. The stronger reducing agent sodium borohydride resulted in higher gold loading, with the loading being higher in the Moist lenses due to higher diffusivity of the reducing agent into the lens. However, GNPs were smaller in size and relatively monodispersed in TruEye GoldinLens, resulting in higher cystine uptake of 47 μg/lens over 24 h (vs. 33 μg/lens for Moist GoldinLens). However, the rate of this uptake was higher for Moist GoldiLens (8.25 vs. 2.35 μg/h), with the maximum uptake occurring in one hour (vs. five hours). Conclusion: A method for manufacturing GoldinLens, wherein small gold nanoparticles are trapped in contact lenses, has been developed for drugless cystinosis treatment. The lenses withdraw cystine molecules from the surrounding milieu, with the TrueEye GoldinLens being superior for the extent of, while Moist GoldinLens is superior for rate of cystine removal. GoldinLenses of this study can be used for drugless cystine removal cystinosis treatment with one- or five-hour wear at a time. Keywords: Cystinosis treatment; Gold nanoparticles; Nanoparticle synthesis; Soft contact lens. Copyright © 2021 Elsevier B.V. All rights reserved. Full text links |
| Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis
Trends Mol Med. 2021 May 8;S1471-4914(21)00099-X. doi: 10.1016/j.molmed.2021.04.004. Online ahead of print. Authors Amer Jamalpoor 1 , Amr Othman 1 , Elena N Levtchenko 2 , Rosalinde Masereeuw 3 , Manoe J Janssen 4 Affiliations
Abstract Nephropathic cystinosis is a severe, monogenic systemic disorder that presents early in life and leads to progressive organ damage, particularly affecting the kidneys. It is caused by mutations in the CTNS gene, which encodes the lysosomal transporter cystinosin, resulting in intralysosomal accumulation of cystine. Recent studies demonstrated that the loss of cystinosin is associated with disrupted autophagy dynamics, accumulation of distorted mitochondria, and increased oxidative stress, leading to abnormal proliferation and dysfunction of kidney cells. We discuss these molecular mechanisms driving nephropathic cystinosis. Further, we consider how unravelling molecular mechanisms supports the identification and development of new strategies for cystinosis by the use of small molecules, biologicals, and genetic rescue of the disease in vitro and in vivo. Keywords: CTNS gene; cystinosis; lysosomal storage disorder; renal Fanconi syndrome; therapeutic strategies. Copyright © 2021 Elsevier Ltd. All rights reserved. Conflict of interest statement Declaration of Interests The authors declare no competing interests. Full text links |
| Testicular function in males with infantile nephropathic cystinosis
Hum Reprod. 2021 Apr 20;36(5):1191-1204. doi: 10.1093/humrep/deab030. Authors J Rohayem 1 , D Haffner 2 , J F Cremers 1 , S Huss 3 , J Wistuba 4 , D Weitzel 5 , S Kliesch 1 , K Hohenfellner 5 Affiliations
Free PMC article Abstract Study question: Do males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood? Summary answer: Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood. What is known already: Biallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC. Study design, size, duration: In this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function. Participants/materials, setting, methods: Serum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system. Main results and the role of chance: Adherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery. Limitations, reasons for caution: Limitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes. Wider implications of the findings: This study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood. Study funding/competing interest(s): This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare. Trial registration number: n/a. Keywords: biologic paternity; endocrine testicular function; fatherhood; juvenile nephropathic cystinosis; semen quality. © The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. Full text links |
| A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers
Pharmacol Res Perspect. 2021 Apr;9(2):e00739. doi: 10.1002/prp2.739. Authors Cécile L Berends 1 2 , Lisa Pagan 1 2 , Michiel J van Esdonk 1 , Naomi B Klarenbeek 1 2 , Kirsten R Bergmann 1 , Matthijs Moerland 1 2 , Vincent van der Wel 3 , Saco J de Visser 4 , Hans Büller 5 , Frans de Loos 5 , Wouter S de Vries 6 , Hans Waals 6 , Leo G J de Leede 7 , Jacobus Burggraaf 1 2 , Ingrid M C Kamerling 1 2 Affiliations
Free PMC article Abstract The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18). Keywords: compliance; cystagon; cysteamine; cystinosis; sustained-release. © 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Conflict of interest statement The trial was initiated by Fair Medicine, a Foundation with the aim to develop affordable drugs and represented by its employees H Büller and F de Loos. Fair Medicine participates in Patient One BV. The trial was sponsored by Patient One BV, which is owned by a coalition of companies and institutions and represented by V van der Wel. L G J de Leede is the owner of Exelion BV, which participates in Patient One BV. Medication was prepared by Tiofarma BV represented by its employees W S de Vries and H Waals. H Waals owns shares of Tiofarma BV, which participates in Patient One BV. The study was designed and carried out by the foundation Centre for Human Drug Research that was supported by a grant of Patient One BV. C L Berends, L Pagan, M J van Esdonk, N B Klarenbeek, K R Bergmann, M Moerland, S J de Visser, J Burggraaf, and I M C Kamerling have nothing to disclose. Full text links |
| Non-invasive intradermal imaging of cystine crystals in cystinosis
PLoS One. 2021 Mar 4;16(3):e0247846. doi: 10.1371/journal.pone.0247846. eCollection 2021. Authors Marya Bengali 1 , Spencer Goodman 1 , Xiaoying Sun 2 , Magdalene A Dohil 3 , Ranjan Dohil 4 , Robert Newbury 5 , Tatiana Lobry 1 , Laura Hernandez 1 , Corinne Antignac 6 7 , Sonia Jain 2 , Stephanie Cherqui 1 Affiliations
Free PMC article Abstract Importance: Development of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation. Objective: To develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status. Design, setting and participants: 101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children’s Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up. Exposures: Intradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies. Main outcomes and measures: The primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV’s possible predictive potential. Results: Over 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 μm3 [1169.1] for patients vs. 363.1 μm3 [194.3] for controls, P<0.001). Medical outcome data was collected from 43 patients with infantile cystinosis (media [range] age: 11 yrs [0.8, 54]; 51% female). nCCV was positively associated with hypothyroidism (OR = 19.68, 95% CI: [1.60, 242.46], P = 0.02) and stage of chronic kidney disease (slope estimate = 0.53, 95%CI: [0.05, 1.00], P = 0.03). Conclusions and relevance: This study used non-invasive RCM imaging to develop an intradermal cystine crystal quantification method. Results showed that cystinosis patients had increased nCCV compared to healthy controls. Level of patient nCCV correlated with several clinical outcomes suggesting nCCV may be used as a potential new biomarker for cystinosis to monitor long-term disease control and medication compliance. Conflict of interest statement I have read the journal’s policy and the authors of this manuscript have the following competing interests: Stephanie Cherqui is inventor on a patent entitled “Methods of treating mitochondrial disorders” (#20378-201301) and co-inventor on a patent entitled “Methods of treating lysosomal disorders” (#20378-202488). She is a cofounder, shareholder and a member of both the Scientific Board and Board of Directors of Stelios Therapeutics Inc. Stephanie Cherqui also serves as a member of the Scientific Review Board and Board of Trustees of the Cystinosis Research Foundation. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no other patents, products in development or marketed products associated with this research to declare. Full text links |
| A sustained release cysteamine microsphere/thermoresponsive gel eyedrop for corneal cystinosis improves drug stability
Drug Deliv Transl Res. 2021 Feb 4. doi: 10.1007/s13346-020-00890-6. Online ahead of print. Authors Jorge Jimenez 1 , Michael A Washington 2 , Jayde L Resnick 2 , Ken K Nischal 2 3 , Morgan V Fedorchak 4 5 6 7 8 Affiliations
Abstract Cystinosis is a rare, metabolic, recessive genetic disease in which the intralysosomal accumulation of cystine leads to system wide organ and tissue damage. In the eye, cystine accumulates in the cornea as corneal cystine crystals and severely impacts vision. Corneal cystine crystals are treated with cysteamine eyedrops when administrated 6 to 12 times day and used within 1 week. The strict dosing regimen and poor stability are inconvenient and add to the burden of therapy. To reduce the dosing frequency and improve the stability, we present reformulation of cysteamine into a novel controlled release eyedrop. In this work, we characterize and evaluate a topical drug delivery system comprised of encapsulated cysteamine in polymer microspheres with a thermoresponsive gel carrier. Spray-dried encapsulation of cysteamine was performed. In vitro cysteamine release, stability, and ocular irritation and corneal permeation were evaluated. The data suggest that encapsulated cysteamine improves the stability to 7 weeks when compared with 1-week aqueous cysteamine eyedrops. Release studies from one drop of our system show that cysteamine release was present for 24 h and above the minimum cysteamine eyedrop amount (6 drops). Cysteamine from our system also resulted in negligible irritation and enhanced permeation when compared with traditional cysteamine eyedrops. In vivo studies were implemented to support ease of administration, tolerability, and retention for 24 h. These studies suggest that our controlled release delivery system may provide stable cysteamine from a safe, once daily gel eyedrop. Keywords: Cornea; Ocular drug delivery; PLGA microspheres; Rare disease; Thermoresponsive gel. Full text links |
| Towards Modelling Genetic Kidney Diseases with Human Pluripotent Stem Cells
Nephron. 2021;145(3):285-296. doi: 10.1159/000514018. Epub 2021 Mar 26. Authors Kirsty M Rooney 1 , Adrian S Woolf 1 2 , Susan J Kimber 1 Affiliations
Free article Abstract Background: Kidney disease causes major suffering and premature mortality worldwide. With no cure for kidney failure currently available, and with limited options for treatment, there is an urgent need to develop effective pharmaceutical interventions to slow or prevent kidney disease progression. Summary: In this review, we consider the feasibility of using human pluripotent stem cell-derived kidney tissues, or organoids, to model genetic kidney disease. Notable successes have been made in modelling genetic tubular diseases (e.g., cystinosis), polycystic kidney disease, and medullary cystic kidney disease. Organoid models have also been used to test novel therapies that ameliorate aberrant cell biology. Some progress has been made in modelling congenital glomerular disease, even though glomeruli within organoids are developmentally immature. Less progress has been made in modelling structural kidney malformations, perhaps because sufficiently mature metanephric mesenchyme-derived nephrons, ureteric bud-derived branching collecting ducts, and a prominent stromal cell population are not generated together within a single protocol. Key Messages: We predict that the field will advance significantly if organoids can be generated with a full complement of cell lineages and with kidney components displaying key physiological functions, such as glomerular filtration. The future economic upscaling of reproducible organoid generation will facilitate more widespread research applications, including the potential therapeutic application of these stem cell-based technologies. Keywords: Embryo; Gene; Glomerulus; Kidney disease; Organoid; Tubule. © 2021 The Author(s) Published by S. Karger AG, Basel. Full text links |
| HK022 bacteriophage Integrase mediated RMCE as a potential tool for human gene therapy
Nucleic Acids Res. 2020 Dec 16;48(22):12804-12816. doi: 10.1093/nar/gkaa1140. Authors Amer Elias 1 , Hala Kassis 1 , Suha Abd Elkader 1 , Natasha Gritsenko 1 , Alessio Nahmad 1 , Hodaya Shir 1 , Liana Younis 1 , Atheer Shannan 1 , Hideki Aihara 2 , Gali Prag 1 , Ezra Yagil 1 , Mikhail Kolot 1 Affiliations
Free PMC article Abstract HK022 coliphage site-specific recombinase Integrase (Int) can catalyze integrative site-specific recombination and recombinase-mediated cassette exchange (RMCE) reactions in mammalian cell cultures. Owing to the promiscuity of the 7 bp overlap sequence in its att sites, active ‘attB’ sites flanking human deleterious mutations were previously identified that may serve as substrates for RMCE reactions for future potential gene therapy. However, the wild type Int proved inefficient in catalyzing such RMCE reactions. To address this low efficiency, variants of Int were constructed and examined by integrative site-specific recombination and RMCE assays in human cells using native ‘attB’ sites. As a proof of concept, various Int derivatives have demonstrated successful RMCE reactions using a pair of native ‘attB’ sites that were inserted as a substrate into the human genome. Moreover, successful RMCE reactions were demonstrated in native locations of the human CTNS and DMD genes whose mutations are responsible for Cystinosis and Duchene Muscular Dystrophy diseases, respectively. This work provides a steppingstone for potential downstream therapeutic applications. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. Full text links |
| Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives
Pharmaceutics. 2020 Dec 3;12(12):1177. doi: 10.3390/pharmaceutics12121177. Authors Ana Castro-Balado 1 2 3 , Cristina Mondelo-García 1 2 , Iria Varela-Rey 1 2 3 , Beatriz Moreda-Vizcaíno 3 , Jesús F Sierra-Sánchez 4 , María Teresa Rodríguez-Ares 5 , Gonzalo Hermelo-Vidal 2 , Irene Zarra-Ferro 1 2 , Miguel González-Barcia 1 2 , Eva Yebra-Pimentel 6 , María Jesús Giráldez-Fernández 6 , Francisco J Otero-Espinar 3 , Anxo Fernández-Ferreiro 1 2 Affiliations
Free PMC article Abstract Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs. Although renal damage prevails during initial stages, the deposition of cystine crystals in the cornea causes severe ocular manifestations. At present, cysteamine is the only topical effective treatment for ocular cystinosis. The lack of investment by the pharmaceutical industry, together with the limited stability of cysteamine, make it available only as two marketed presentations (Cystaran® and Cystadrops®) and as compounding formulations prepared in pharmacy departments. Even so, new drug delivery systems (DDSs) need to be developed, allowing more comfortable dosage schedules that favor patient adherence. In the last decades, different research groups have focused on the development of hydrogels, nanowafers and contact lenses, allowing a sustained cysteamine release. In parallel, different determination methods and strategies to increase the stability of the formulations have also been developed. This comprehensive review aims to compile all the challenges and advances related to new cysteamine DDSs, analytical determination methods, and possible future therapeutic alternatives for treating cystinosis. Keywords: analytical chemistry methods; cysteamine; cystinosis; drug delivery systems; ophthalmic administration. Conflict of interest statement The authors declare no conflict of interest. Full text links |
