Research

Deciphering the molecular basis for how combination Cysteamine/Everolimus treatment protects against kidney damage in cystinotic rats - Dr Jennifer Hollywood and Dr Alan Davidson, University of Auckland - Amount Awarded €12,000.

The Educational and Psychosocial Experiences of Young People Living with Cystinosis: Barriers, Challenges and Facilitators Experienced Across the Irish Education System – Prof Joyce Senior, UCD – Amount Awarded €20,000.

1. Evaluation of a novel drug combination treatment for nephropathic cystinosis in a new cystinotic rat model – Dr Jennifer Hollywood, University of Auckland. Amount awarded: CI total contribution €99,094. (Total joint funding value: €198,188).

1. Investigating the potential of CTNS-mRNA loaded nanoparticles as a new therapeutic strategy for nephropathic cystinosis - Prof Elena Levtchenko, Amsterdam University Medical Centre. Amount awarded: CI total contribution €76,200. (Total joint funding value: €152,400).

1. Safety and efficacy of cysteamine loaded contact lenses – Prof Anuj Chauhan, Colorado School of Mines, Colorado, US – Amount Awarded: €150,000.  This project is co-funded on a 50:50 basis with Cystinosis Foundation UK.

2. Study of muscular disease in nephropathic cystinosis – Prof Elena Levtchenko, UZ Leuven, BE / Associate Prof Rik Gijsbers KU Leuven, BE – Amount Awarded: €100,000.  This project is co-funded on a 50:50 basis with Cystinosis Foundation UK.

3. Clinical and Molecular Assessments of Male Infertility in Cystinosis – Prof Minnie Sarwal, UCSF, California, US – Amount Awarded: €300,000.  This project is co-funded on a 50:50 basis with Cystinosis Research Network (US).

1. Serum IgG Glycosylation in Cystinosis (SIGIC) – Prof Atif Awan, CUH Temple Street & Dr Roisin O’Flaherty, NUI Maynooth, Ireland – Amount Awarded €10,000.

2. Generation of CTNS and MFSD12 double knockout induced pluripotent stem cell lines to test if MFSD12 is a candidate therapeutic target for a new class of cystinosis drugs – Dr Jennifer Hollywood,  University of Auckland –  Amount Awarded €10,216.

3. New solid forms of cysteamine therapeutics – Dr Oisín Kavanagh Amount, Newcastle University. Amount Awarded €10,000.

1. Literature review of cystinosis and key areas – Michael Deane, University College Cork, IE – Award Amount: €4,356 (Summer studentship)

2. IMPACT Study – Dr Katharina Hohenfellner, Klinik für Kinder- und Jugendmedizin – Kindernephrologie, DE – Award Amount: €20,000

3. Biomaterial-mediated delivery of CTNS gene for ocular cystinosis – Dr Valeria Graceffa, Institute of Technology, Sligo, IE – Award Amount: €9,990

1. Characterisation of a novel cystinosin transporter knockout rat model – Dr Manoe Janssen, University of Utrecht, NL – Award Amount: €10,000

2. A pilot study to holistically target dysfunctional pathways in cystinosis: Drug repurposing with gene expression connectivity mapping – Dr Shu-Dong Zhang, University of Ulster, Northern Ireland – Award Amount: €9,908

3. Endogenous tagging of CTNS using CRISPR/Cas9 – Professor Elena Levtchenko, UZ Leuven, Belgium – Award Amount: €10,000

1. Targeting Autophagy in Nephropathic Cystinosis: generation of CTNS mutant cell lines by CRISPr/Cas9 gene editing – Dr James Murray, TCD, Ireland and Professor Minnie Sarwal, University of California, San Francisco, USA – Award Amount: €8,600

2. Characterisation of a novel cystinosin transporter knockout rat model – Dr Jennifer Hollywood, University of Auckland, NZ – Award Amount: €10,000

1. Dose Escalation Study to Demonstrate Safety of Cysteamine Releasing Contact Lens – Professor Anuj Chauhan, University of Florida, USA – Award Amount: €10,000

1. Unravelling the mechanisms of azoospermia and potential future treatments in male cystinosis patients – Professor Elena Levtchenko, UZ Leuven, Belgium – Award Amount: €200,000

2. Targeting Autophagy in Nephropathic Cystinosis – Professor Minnie Sarwal, University of California, San Francisco, USA – Award Amount: €300,000

1. Drug Eluting Contact Lenses for Cystinosis Therapy – Professor Anuj Chauhan, University of Florida, USA – Award Amount: €72,000

2. Modelling Cystinosis with Human Stem Cells and the Therapeutic Potential of Aspartate – Professor Alan Davidson, University of Auckland, NZ and Dr Patrick Harrison, University College Cork, Ireland – Award Amount: €288,000

Residual Cystine Transport Activity for Specific Infantile and Juvenile CTNS Mutations in a PTEC-Based Addback Model.

• There is the suggestion that CTNS exerts additional functions besides cystine transport. This study investigated the impact of infantile and juvenile CTNS to better understand the link between genotype and CTNS function. The findings shed new light on CTNS mutations, highlighting the need for robust assessment methodologies in clinically relevant cellular models and thus paving the way for better stratification of cystinosis patients, and advocating for the development of more personalized therapy. Part funded by Cystinosis Ireland.  Learn More

Plasma chitotriosidase enzyme activity as a novel therapeutic monitor for cysteamine treatment in nephropathic cystinosis: A retrospective validation study.

• The authors previously proposed chitotriosidase enzyme activity as a potential novel biomarker for the therapeutic monitoring of cysteamine treatment in cystinosis. In this study, they aimed to validate their previous findings and to confirm the value of chitotriosidase in the management of cystinosis therapy. Plasma chitotriosidase enzyme activity significantly correlated with WBC cystine levels, cysteamine total daily dosage and a Composite compliance score. Moreover, plasma chitotriosidase was a significant independent predictor for WBC cystine levels. Chitotriosidase enzyme activity is a valid potential alternative biomarker for monitoring cysteamine treatment in nephropathic cystinosis patients. Learn More

MFSD12 depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.

• MFSD12 is a lysosomal cysteine importer, that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, the authors aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. MFSD12 mRNA depletion reduced cystine levels in both patient derived ciPTEC (CTNSΔ57kb) and zebrafish models without improvement of the proximal tubular function in the ctns-/- zebrafish embryo. Further evaluation is needed. Learn More

Switching from immediate- to extended-release cysteamine in patients with nephropathic cystinosis: from clinical trials to clinical practice.

• The purpose of this study was to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Nine patients (four children, five adults)were included 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population. Learn More 

Nlrp2 deletion ameliorates kidney damage in a mouse model of cystinosis.

• The authors presented data to indicate that Nlrp2 (a protein part of the inflammasome complex, which plays a crucial role in innate immunity) is a potential pharmacological target for delaying progression of kidney disease in cystinosis.  They observed that although genetic ablation of Nlrp2 did not abolish the development of Fanconi syndrome or renal parenchymal lesions, it did delay it. Learn More

CTNS Mutations Causing Autosomal Recessive Cystinosis in a Subset of Iranian Population: Report of Two New Variants.

• This study aimed to investigate the mutations of the CTNS gene in 20 Iranian patients suffering from Nephropathic Cystinosis. At first, the authors searched for the 57 kb deletion, but none of the 20 patients had it. Two new mutations, c.971972insC and c.956956delA, which have not been reported before, were found. The other mutations were those previously reported/found. Learn More

Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients.

• The objective of this report was to identify and characterize cases of fibrosing colonopathy (a condition that effects the colon casing it to swell, shorten and scar), a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. The authors looked at 4 cases of fibrosing colonopathy reported with the use of cysteamine DR and prompted regulatory action by the FDA. Healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment. Learn More

A Comparative Pharmacokinetic Study for Cysteamine-Containing Eye Drops as an Orphan Topical Therapy in Cystinosis.

• This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization, as well as ex vivo tests, well supported by statistical analysis since the only available eye drops Cystadrops® are scare and commercially available with strong limitations. The results show that the physicochemical properties (viscosity, mucoadhesivity, dissolution, and lipid membrane permeability) of Cystadrops® are more favourable than CYA-CED regarding expected pharmacokinetic properties that are relevant in the ophthalmic approach. However, the nearly equivalent ex vivo pharmacokinetic profile obtained in studies on porcine eyes suggests that CYA-CED can serve as a suitable alternative in case of difficulty in supplying Cystadrops®, which can reduce the risk of possible interruptions in patient care. Learn More

Renal transplantation for infantile and juvenile cystinosis: Two case report and review of the literature.

• Detailed reports on preoperative and Long-term postoperative management in kidney transplant (KT) patients remain sparse. This report discusses the outcomes of two young adult patients of Middle Eastern descent with cystinosis who underwent KT. Following KT, both patients experienced regained renal function, resolution of extrarenal complications, and normalization of laboratory parameters. Furthermore, both patients showed excellent postoperative outcomes with no acute rejection or allograft-related complications. KT is the treatment of choice for cystinosis patients with ESRD. Long-term follow-up post-transplantation is crucial to maintain good graft function. Further studies may elucidate optimal pre- and postoperative management protocols for this rare condition.             Learn More

Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives.

• There is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. The aim was to review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines. The authors wrote an array of issues and in the end they suggested: Given the profound impact of GI symptoms and the complexity of untangling and addressing their many causes, three key imperatives emerged from this review and discussionLearn More

Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

• This study examined whether inhibiting the megalin pathway in adult cystinotic mice by dietary supplementation with lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Results showed dietary manipulation, with both supplements, of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo. Learn More

The effects of transitioning from immediate release to extended release cysteamine therapy in Norwegian patients with nephropathic cystinosis: a retrospective study.

• This was a long-term study that explored the effects of transitioning from immediate release (IR) (Cystagon®, Recordati Rare Diseases, Puteaux, France) to extended release (ER) (Procysbi®, Horizon Therapeutics, USA, and Chiesi Farmaceutici S.p.A, Parma, Italy) formulation in 10 Norwegian patients in routine clinical care. The results indicate that switching from IR- to ER-cysteamine was feasible and well tolerated under routine clinical practice. ER-cysteamine allowed satisfactory disease control over the long period considered. Learn More   

Lysosomal cystine export regulates mTORC1 signalling to guide kidney epithelial cell fate specialization.

• This study identified mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis. Learn More

Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients.

• The authors describe a consensus-based guidance to support the management of adolescents and adults living with cystinosis. The topics covered are advice on fertility and family planning, consideration of the nervous, muscular, ophthalmic, cardio-respiratory, endocrine, dermatological and gastrointestinal systems, as well as guidance on dental care, diet, lifestyle, and improving quality of life and psychological well-being. In summary, this work outlines recommendations and a checklist for clinicians with a vision for improving and standardizing the multidisciplinary care for patients with cystinosis.  Learn More

Gastrointestinal Manifestations of Adult Cystinosis in Iran: A Descriptive Study.

• This study discusses the importance of immediate diagnosis and early treatment of the disease with cystagon, which reduces gastrointestinal complications in such patients. Early diagnosis and treatment with the proper dose of cystagon can increase life expectancy, reduce complications, and improve the patient's quality of life. Learn More

Nephropathic cystinosis (NC) in Poland: a 40-year retrospective study.

• This was an evaluation of prevalence, genetic background and clinical course of NC in a Polish population. The authors concluded to say the prevalence of NC is much lower than in Western countries and its molecular background appears to be different. The unfavourable course in a majority of INC patients was caused by a limited access to the cysteamine treatment.  Learn More

Fertility in Cystinosis.

• The majority of male cystinosis patients are infertile due to azoospermia, in contrast to female patients who are fertile. In this review, the authors provide a state-of-the-art overview on the available clinical, histopathological, animal, and in vitro data. They summarize current insights on both cystinosis males and females, and their clinical implications including the potential effect of cysteamine on fertility. In addition, they identify the remaining challenges and areas for future research.Learn More

Hematopoietic Stem Cell Gene Therapy for Cystinosis: From Bench-to-Bedside.

• The current treatment for cystinosis is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns-/- mice, the authors first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. In this review, the authors describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis. Learn More

In Vitro and In Vivo Models to Study Nephropathic Cystinosis.

• This review provides an overview of the in vitro and in vivo models available to study cystinosis, how well they recapitulate the disease phenotype, and their limitations. Learn More