Grants Awarded

Development of a patient-reported outcome to measure the health-related quality of life of children and adolescents with cystinosis. 

Drs. Katharina Hohenfellner and Julia Quitmann

Total project investment is $155, 075.09 over two years.

Patient-Reported Outcome measures (PROM) are questionnaire-based tools that can help healthcare professionals understand the health status or disease burden from the patient’s perspective. These tools can be used to evaluate new therapies or to improve the healthcare provided. Disease-specific instruments that measure health-related quality of life (HrQoL) are particularly informative, as they capture the needs and challenges of specific patient groups particularly well. As a multidimensional construct, HrQoL includes physical, emotional, mental, social, and behavioral components of well-being from the patient’s perspective HrQoL can be measured using four different types of instruments: generic, chronic-generic, condition specific and treatment-specific instruments. Generic questionnaires represent the full range of health conditions, address groups independent of their respective health state and are effective for comparisons between two cohorts (e.g. patients with cystinosis and healthy controls). Chronic-generic instruments are focusing on a chronic condition independent of its specific characteristics, while specific questionnaires are tailored to problems associated with a specific condition (e.g. cystinosis) or treatment (e.g. patients receiving a kidney transplantation). Despite the significant impairments experienced by patients with cystinosis, very few studies investigate HrQoL in this patient group and e disease-specific HrQoL measures are lacking. Thus, the primary aim of this planned study is to develop a PROM for children and adolescents with cystinosis. This instrument will capture the HrQoL from both the child/adolescent and parent perspectives. It will be applicable to clinical trials ranging from randomized clinical trials (RCTs) to surveillance designs, focusing on the impact of cystinosis and its treatment. The preparations have already started. We are currently developing the questionnaire “QUALIFY” (Health-related quality of life of children and adolescents with cystinosis) through intensive literature research and interviews with young German patients and their parents. This preliminary version of QUALIFY needs to be cross-culturally validated in a larger sample (= investigated whether the instrument actually measures what it is supposed to measure) and adapted to the English, Spanish and French language. The study will take place in four phases within a 24-month timeline. Patients and parents will be recruited by both clinicians and patient organizations of the participating countries. In the first phase, the preliminary German version of QUALIFY will be translated into English, French and Spanish. In phase 2, these new versions of QUALIFY will be used in an online pilot test to analyse their preliminary psychometric properties. A cognitive debriefing will be conducted so that patients and parents can reflect on the comprehensibility, completeness, and applicability of the instrument. In the third phase, the refined questionnaires will be applied in an online field test to evaluate their final psychometric properties (incl. internal consistency, convergent validity, reliability). In the fourth phase, a final report and publications for scientific journals will be written. The final product will be a cross-cultural, psychometrically validated, practically feasible, and conceptually suitable instrument for children and adolescents with cystinosis. It will be available in English, Spanish and French for further (inter-)national studies. With further international collaborations, this tool can be linguistically validated and cross-culturally 2 adapted for use in a wide range of countries. Although the project in this grant application refers to the development of PROM for children, the development of a PROM for adult patients is planned as a follow-up project.

FEBRUARY 2021

Grant Awarded February 2021 by the Cystinosis Research Network and Cystinosis Ireland

Perturbations in the V-ATPase Pathway Drive Pathology in the Male Reproductive System in Cystinosis

Principal Investigator Professor Minnie Sarwal, Professor of Surgery, Division of Multi Organ Transplantation, University of California San Francisco (UCSF), USA and co-applicants, Dr James F. Smith, Associate Professor and Director Male Reproductive Health, Department of Urology, University of California, San Francisco and Dr Polina V Lishko, Associate Professor, Department of Molecular and Cell Biology, University of California Berkeley, USA. 

The research project is a total investment of €300,000 from Cystinosis Ireland and CRN (€150,000 each) over the next three years.

Cystinosis is a very rare inherited genetic disease that causes the build-up of cystine, an amino acid is normally present in very small amounts in every single cell of a healthy person. The excess cystine forms sharp crystals that damage the body’s cells.  Many of the body’s organs are affected by cystinosis including the kidneys and the eyes in particular. However in men, there can be an impact on fertility and the ability to produce sperm (azoospermia). Whereas in the past, the life expectancy of men living with cystinosis was short and their physical wellbeing relatively poor, today there are an increasing proportion of men living with cystinosis who are well and who want to consider parenthood.

This research project aims to study the molecular and cellular changes that can cause azoospermia in men with cystinosis. The research will be a first step towards developing an effective treatment that will give men living with cystinosis the opportunity to become fathers. The knowledge generated from this research will also improve our overall understanding of the disease and in particular of certain poorly understood cystinosis symptoms that appear to be caused by malfunctions other than the accumulation of cystine.

In selecting this proposal for co-funding, the Boards of Cystinosis Ireland and CRN agreed that this is a scientifically significant proposal focused on a very important and strategic research topic for cystinosis patients.

This project builds upon research and results generated from two previous projects co-funded by Cystinosis Ireland and the Irish Government’s health research funding agency (the HRB) – a project led by Professor Minnie Sarwal in UCSF, USA entitled “Targeting Autophagy in Nephropathic Cystinosis” and a project led by Professor Elena Levtchenko in UZ Leuven, Belgium entitled “Unravelling the mechanisms of azoospermia and potential future treatments in male cystinosis patients”.

2020 CRN Research Grant Funding

As a result of the 2020 Call for Research Proposals, CRN is proud to announce funding for the following research projects for a total of $436,193 in research grants.

Cognitive Control Systems in Cystinosis

Sophie Molholm, PhD Co-Principal Investigator, John Foxe, PhD Co-Principal Investigator 

Grant Amount: $315,193, two year study

Seminal behavioral studies by Trauner and others in human patients have suggested the presence of cognitive dysfunction in cystinosis. Our own work suggests some behavioral and neural differences and difficulties with sensory memory in this population. However, the neurocognitive phenotype associated with CTNS mutations and its developmental path are still poorly understood, and the prime areas of neurocognitive vulnerability in this population are in need of much more thorough characterization. This is critical to developing effective therapies to compensate for or improve on areas of cognitive vulnerability. To this end, we propose to characterize different components of executive functioning (memory updating, set shifting, conflict monitoring, and inhibition) in cystinosis. Focus on this area is motivated by our previous work, the literature on cognitive weaknesses in cystinosis thus far, and by first person reports collected during interactions with patients and families. We will use high-density electrophysiology (EEG)—a non-invasive method that allows one to directly measure functional brain activity at the millisecond scale and thus reliably assess the integrity of information processing at the neural level—and standardized cognitive functional assessments to test 15 children, 15 adolescents, and 15 adults with cystinosis and the same number of age-matched unaffected healthy controls. Twenty heterozygotes and age matched controls will also be tested to examine the role that mutation versus disease plays in the cognitive phenotype of cystinosis, 

Significance: Greater knowledge of the neurocognitive dynamics of executive function in cystinosis has the potential to critically advance the development of interventions for these individuals. In addition, identification of neural markers will provide objective assays of treatment efficacy on brain function.

Chitotriosidase as a Therapeutic Monitor for Cysteamine Therapy in Cystinosis: a Retrospective Validation Study

Mohamed A. Elmonem, Koenraad R.P. Veys, Lambertus P. van den Heuvel, William A. Gahl, Elena Levtchenko

Grant amount:  $44,000, one year study

Nephropathic cystinosis lacks a practical therapeutic monitor for cysteamine therapy. The currently used white blood cells (WBC) cystine assay, although very specific for the disease, has many clinical and technical drawbacks limiting its routine use in most countries. Chitotriosidase enzyme activity in plasma is a potential alternative to WBC cystine in nephropathic cystinosis monitoring. Chitotriosidase is mainly produced in various tissues by activated macrophages upon stimulation by cystine crystals. We have previously demonstrated that the enzyme is significantly elevated in the plasma of cystinosis patients compared to both healthy and renal controls. Moreover, in a two-year longitudinal study chitotriosidase enzyme activity was a significant independent predictor of WBC cystine levels and was superior to WBC cystine as an indicator of the number of extrarenal complications in cystinosis patients. When compared to WBC cystine, plasma chitotriosidase assay is simpler, faster, more economical and needs a much smaller sample making it more convenient, especially in young children. Furthermore, the enzyme is extremely stable for years at minus zero temperatures. In the current proposal, we plan to validate our results in a large cohort of previously recruited cystinosis patients followed up at the NIH Clinical Center in Bethesda, Maryland, USA. Stored samples at -80°C of 150 cystinosis patients will be retrospectively assayed for chitotriosidase enzyme activity, and will be correlated to documented parameters of kidney function, extra renal complications and a WBC cystine-based long-term compliance score.

IMPACT – Improvement of Motoric Abilities in Patients with Cystinosis

Katharina Hohenfellner, MD

Grant Amount:  $77,000, one year study

The concept presented here, follows the established approach for the rehabilitation of children “Auf die Beine”, which was developed in Cologne for children and adolescents with limited mobility, e.g. caused by cerebral palsy or patients with osteogenesis imperfecta (https://unireha.uk-koeln.de/kinder-jugendreha/behandlungskonzept-auf-die-beine/). The training design with home exercise and short training sessions considers the fact that the target patient group is already under great strain due to the severity of the disease (medication, special diet, possibly dialysis). The project follows the official recommendations for the use of a vibration plate (4,5). Patients train with Galileo vibration plates according to a fixed training schedule which provides for 10 short training sessions per week (maximum 2 per day). Within one training session, four exercises will be performed. The control group will perform the same exercises without vibration plates, but with dumbbells. Patients will initially undergo an intensive training course and will receive regular supervision during the three-month home training phase. The study is designed as a randomized controlled trial. Due to the very rare underlying disease a matched pair design was chosen to achieve comparability between the two groups. The patients will be matched based on their age, sex, and major previous surgeries. A baseline and two follow-up clinical assessment, one after the three-month home training phase and one after the follow-up phase, will take place. The primary endpoint is the change in muscle strength (in %) from the baseline examination to the measurement after the training phase. In the control group (CG), a mean shift of 0 % is expected, since no vibration training is carried out.

Potential Impact for patients with Cystinosis:

Patient orientation: empowering patients by supporting an active lifestyle and enabling patients to positively influence the course of the disease themselves. Optimization of clinical outcomes: improving cardiorespiratory performance and increasing muscle strength in patients. Improvement of patient-oriented end points of care: improving quality of life.

Grant Awarded July 2020 by the Cystinosis Research Network and Cystinosis Ireland

A Cellular Resource for Studying Male Infertility in Cystinosis, Minnie Sarwal, MD, PhD, Professor of Surgery, (Director, Precision Transplant Medicine) University of California San Francisco (UCSF), James Smith, MD, MS (Director, Male Reproductive Health Center Urologist), University of California San Francisco (UCSF), Ann Harris, Professor, Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, Elena Levchenko, Professor, Department of Pediatric Nephrology, Leuven, EU, and Swastika Sur, MSc., PhD Postdoctoral Scholar, Sarwal Lab, University of California San Francisco, Department of Surgery.

Total Grant: €10,000

Principal Investigator, Swastika Sur, a Postdoctoral Fellow at the University of California San Francisco, has outlined a research proposal focused on infertility in men with cystinosis.

In addition to various endocrine organs that are affected in cystinosis, hypergonadotropic hypogonadism has been reported as a frequent finding in male cystinosis patients. Although spermatogenesis has shown to be intact at the testicular level in some patients, no male cystinosis patient is known to have naturally fathered a child. The sole treatment for cystinosis is the aminothiol cysteamine, which is highly effective in reducing the intracellular levels of cystine. However, this drug is ineffective in the treatment of male infertility in these patients.

A previous study of the pathophysiology of cystinosis-mediated infertility used a CTNS-/- mouse model. However, the CTNS-/- mouse model generated on C57BL/6 background was found to not be suitable for clarifying the pathogenesis of male infertility in cystinosis. This mouse model partially mimics the renal phenotype of the human disease but was found to have normal testicular morphology and function.

Therefore to this date, the exact pathophysiology of male infertility observed in patients with cystinosis is not yet fully understood, which is a critical unmet need due to the growing population of cystinosis patients, treated with cysteamine reaching young adulthood.

This project proposes to generate isogenic immortalized epididymis and testicular cell models to study infertility associated with cystinosis, by using CRISPR/Cas9 technology to develop a deletion in the CTNS gene of normal human epididymis and testicular cells. The Sarwal group’s ongoing collaborations with Dr Smith at UCSF has enabled access to a rich tissue resource of normal testicular and epidydymal samples that will be used for generating this cystinosis- specific resource. The Sarwal research group also has ethical approvals in place at UCSF and at KU Leuven that will allow Dr Sur to approach cystinotic patients for access to patient biosamples.

Previously, the Sarwal research group successfully generated human immortalized CTNS-/- proximal tubular epithelial cells, and confirmed the phenotype of these newly developed cell line in terms of intracellular cystine levels by HPLC-MS/MS.

In this project, Dr Sur will focus on generating human immortalized CTNS-/- epididymal and testicular cells, followed by phenotype validation so that these cell lines can serve as a resource for the research community to study the pathophysiology of male infertility observed in cystinosis.

The Specific Aims of this project are the following:

• Aim 1: Generate human immortalized CTNS -/- epididymal and testis cell lines by CRISPR/Cas9 and confirm the phenotype to further downstream study of male fertility associated with cystinosis
• Aim 2: Map the molecular perturbations in both cell lines with deletion of CTNS and in tissue samples from male cystinotic patients, by using state of the art genomics that the Sarwal Lab has legacy expertise-in. This will define the clinical utility of the resource generated in Aim 1.

This project will provide a first of its kind human cellular models to study cystinosis-mediated male infertility.

CRN Research Funding Update Q4 2018

Grant Awarded October 2018

Study of Neuronal Structure and Function Changes in Cystinosis, John Foxe, PhD and Krishnan Padmanabhan, PhD

Department of Neuroscience Ernst J. Del Monte Institute for Neuromedicine, University of Rochester School of Medicine and Dentistry, Rochester, NY

Year One: $110,000 Total Grant: $110,000

Investigators at the Department of Neuroscience Ernst J. Del Monte Institute for Neuromedicine, University of Rochester School of Medicine and Dentistry Rochester, NY have outlined a research proposal taking a novel systems neuroscience strategy to address the link between molecular/cellular pathology of the lysosomal system in neurons and the resultant changes in the structure and function of neuronal circuits using new electrophysiology, imaging and computational methods to understand the effect of cystinosis on neural circuits. By identifying the mechanisms underlying the neuropathology of the disease at the basic science level, this research program will provide important biomarkers for tracking disease progression, could identify new sites/targets for intervention and guide in the development of strategies for treatment. Following is a brief update on their project: The aim of our research study is to understand how changes at the level of cells in the brain due to lysosomal storage dysfunction translate to changes in cognitive function and behavior. To study the neurobiological underpinnings of cystinosis, the lab uses a Ctns -/- mouse line which has a cystinosis, nephropathic, targeted mutation 1 in the gene. To do this, we have developed new technologies from recording the electrical activity of the brain in this model. Specifically, we have deployed a method for studying the physiology of individual neurons throughout the brain in awake behaving animals. This cutting edge research approach will allow us to identify the neurophysiological changes that arise from the Ctns -/- mouse and relate this to alterations in global brain dynamics. The ultimate goal being to discovery biomarkers of the disease and identify potential targets for subsequent intervention. In the first 6 months of this research project, we have successfully recruited and trained an MD/PhD student with interests in Neurology and development to perform surgeries and record from control mice to characterize baseline patterns of activity throughout the brain for comparison with the Ctns -/- mouse.

Altered protein kinase signaling as a cause of reduced adhesion and increased motility of renal epithelial cells in Cystinosis – E. Ivanova, L. van den Heuvel, E Levtchenko (Principal Investigator) Katholieke Universiteit Leuven, Belgium

Year Two: $88,493 Total Grant: $165,494

Cystinosis is a genetic disease manifesting early in life (≈ 6-12 months) with progressive kidney disease resulting in renal failure early during childhood if not treated. In cystinosis the metabolism of the amino acid cystine is defective leading to its accumulation in the kidney and other organs. This cystine accumulation results in cellular damage and death, but the direct mechanisms beyond this phenomenon are largely unknown. Some harmful cellular events in cystinosis might not be directly related to cystine accumulation and are the subject of our research project. Based on our previous work we hypothesized that the loss of highly specified renal cells like glomerular podocytes and renal proximal tubular cells in urine is a major mechanism causing renal pathology of cystinosis. Increased rate of cellular abundance in urine can be explained by either the decreased adhesion of renal cells to their matrix or their increased motility or by a combination of both mechanisms. Indeed we demonstrated that both events occur in cultured human renal cells derived from cystinosis patients. We further tried to explore the mechanisms beyond this cellular loss. It has been reported in other diseases that increased cell motility and defective adhesion can be associated with the altered protein kinase signaling. In cystinotic podocytes we found an increased expression of activated or phosphorylated Akt kinases compared to control cells. This could explain, at least partially, the abnormal phenotype. We are currently testing other protein kinases that might contribute to this mechanism. In addition we tested the gene expression of several integrin in podocytes, as podocytes adhere to the extracellular matrix using integrin receptors. Although only minor differences were found between cystinotic and control cells, cell surface expression of these proteins still has to be studied. So far most of our experiments were done in podocytes. We recently started to investigate proximal tubular epithelial cells which also showed an increased expression of phosphorylated Akt kinases unifying the concept of the hypothesis over different renal cell types. Our future plan includes also the experimentation with different kinase inhibitors to explore if they can reverse abnormal renal phenotype.

Mechanisms Underlying Neurocognitive Changes in Cystinosis, John Foxe, PhD Co‐Principal Investigator, Sophie Molholm, PhD Co‐Principal Investigator, Steven U. Walkley, DVM, PhD Co‐Principal Investigator Departments of Neuroscience and Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY

Year three: $100,980 Total Grant: $467,950

Travel Addendum: $38,352

The goal of this proposal continues to focus on brain-related changes in the lysosomal disease, cystinosis, through the use of complementary state-of-the-art neurocognitive studies (in cystinosis patients, Aim 1), cell biological analyses and possible treatment strategies (in the mouse model, Aims 2-3). Progress through year 02 of the proposal are outlined below.

AIM 1: To explore sensory processing and multisensory integration as potential biomarkers using high-density electrophysiological mapping techniques in individuals with cystinosis.

This section of the report details progress in the human arm of the CRN project entitled – “Mechanisms Underlying Neurocognitive Changes in Cystinosis”. Under this arm of the project, our main aim was to “explore sensory processing and multisensory integration as potential biomarkers using high-density electrophysiological mapping techniques in individuals with Cystinosis”. Therefore, initially, we recorded high-quality data from 7 patients with Cystinosis while they responded to a sensory processing task. We performed preliminary analyses of those data, compared the outcomes to similar recordings in another lysosomal disorder (Niemann-Pick-C (NPC); N=17) and to an already collected extensive normative dataset recorded from a cohort of matched neurotypical control participants (N=84). The most surprising aspect of those results was the strikingly “normal” patterns of multisensory behavior and neurophysiological responses that we obtained in Cystinosis, in stark contrast to those obtained in the NPC population. As a consequence of this finding, we decided to apply additional paradigms that tap into sensory processing and executive functions, which, based on the clinical phenotype of individuals with Cystinosis, are likely to provide sensitive brain measures of neural function/dysfunction in the Cystinosis population. In this second phase, we have collected data from 32 patients with Cystinosis and from 37 neurotypical control participants and performed analyses of part of the behavioral and the electrophysiological data. In this cumulative report, we indicate major progress over the past six months, since our last report, with blue font.

Scientific communications: We presented preliminary analyses of the data at the Cystinosis Research Network Family Conference in Utah. We also presented these data at the Pediatrics Research Day and at the Lysosomal Rounds at the Albert Einstein College of Medicine and to our Lysosomal Storage Disorders Grand Rounds at Einstein/Montefiore group (April 2018), and will present them at the International Meeting of the Psychonomic Society taking place in the Netherlands (May 2018). We have started preparing the data from two of the datasets for publication, and are currently working on the first manuscript.

Recruitment Efforts: We engaged in extensive recruitment efforts through social media and during the Cystinosis Research Network Family Conference. Furthermore, enrollment capacity was greatly increased through the addition of funds from the CRN to fly families in for two days of data collection. We have met our new recruitment targets and have completed data collection. In the past year and a half, we collected data from 32 individuals diagnosed with cystinosis (19 children, 6 adolescents, and 5 adults) and from 37 neurotypical controls (16 children, 12 adolescents, and 9 adults). We propose to collect data from 9 more adults and 8 more adolescents with Cystinosis (plus healthy age matched controls) so that we may assess how perceptual and cognitive functions change over development in Cystinosis.

CRN Research Funding Update Q3 2017

September 2017 Grant Awarded

Study of Neuronal Structure and Function Changes in Cystinosis, John Foxe, PhD and Krishnan Padmanabhan, PhD

Investigators at the Department of Neuroscience Ernst J. Del Monte Institute for Neuromedicine University of Rochester School of Medicine and Dentistry Rochester, NY have outlined a research proposal taking a novel systems neuroscience strategy to address the link between molecular/cellular pathology of the lysosomal system in neurons and the resultant changes in the structure and function of neuronal circuits using new electrophysiology, imaging and computational methods to understand the effect of Cystinosis is on neural circuits. By identifying the mechanisms underlying the neuropathology of the disease at the basic science level, this research program will provide important biomarkers for tracking disease progression, could identify new sites/targets for intervention and guide in the development of strategies for treatment.

CRN Research Funding Update Q1 2017

March 2017 Grants Awarded

Year Two Study Extensions Announced

We are pleased to announce the CRN’s extended funding to support two ongoing studies. One with Principal Investigator Steven Walkley, DVM, PhD researching the affiliation between Cystinosis and brain function and the second led by Elena Levtchenko, MD, PhD to determine if potential harmful cellular events in Cystinosis may not be directly related to cystine accumulation.

Mechanisms Underlying Neurocognitive Changes in Cystinosis, John Foxe, PhD Co‐Principal Investigator, Sophie Molholm, PhD Co‐Principal Investigator, Steven U. Walkley, DVM, PhD Co‐Principal Investigator

Cystinosis has long been known for its significant impact on renal and thyroid function. It is only in recent years, however, due to the emergence of effective life-prolonging treatment regimens for these primary clinical symptoms that researchers and clinicians have been able to turn greater attention to the impacts this disease has on brain function. To date there is only limited work in this area. To address this shortcoming of knowledge, investigators in Pediatrics and Neuroscience at the Albert Einstein College of Medicine (Molholm, Walkley) and the University of Rochester Medical Center (Foxe) are evaluating individuals with Cystinosis as well as mice in which the Cystinosis gene has been knocked out. The human studies involve the use of high-density electroencephalographic (EEG) recordings of brain activity being carried out by Drs. Molholm and Foxe in Einstein’s Cognitive Neurophysiology Laboratory. Dr. John Foxe, lead investigator on the human project, reports observing a strikingly “normal” pattern of multisensory behavior and brain responses in Cystinosis, a finding that stands in stark contrast to those obtained in another lysosomal storage disorder where significant impairment is observed (Niemann-Pick type C disease). The group will continue to collect data for this study, to see if this finding holds up in a larger sample. In addition, following these “positive” results indicating intact sensory processing, they are turning to measurement of cognitive processes that require highly coordinated activity across extensive networks of cortical regions, as these are likely to be more sensitive to any neural damage incurred. For the mouse studies, spearheaded by Dr. Walkley, director of Einstein’s Sidney Weisner Laboratory of Genetic Neurological Disease, mice with genetically-induced Cystinosis have been established in a breeding colony and are being evaluated for changes in selected brain regions (hippocampus, neocortex and cerebellum) in an attempt to determine with greater precision just how this genetic disease impacts the function of individual types of brain cells. Analyses here range from exploring connectivity and the structure of individual neurons to changes in the metabolic activities secondary to the disease-induced defect in lysosomes. As phenotypic biomarkers related to Cystinosis are identified in these brain regions, the impact of treatment (e.g., with cysteamine) in preventing, delaying and/ or reversing these changes will be pursued. The ultimate goal of these tightly collaborative studies from the two labs is to more fully understand the effects that Cystinosis has on brain structure and function and how factors leading to such compromise could be alleviated.

Altered protein kinase signaling as a cause of reduced adhesion and increased motility of renal epithelial cells in Cystinosis – E. Ivanova, L. van den Heuvel, E Levtchenko (Principal Investigator)

Cystinosis is a genetic disease manifesting early in life (≈ 6-12 months) with progressive kidney disease resulting in renal failure early during childhood if not treated. In Cystinosis the metabolism of the amino acid cystine is defective leading to its accumulation in the kidney and other organs. This cystine accumulation results in cellular damage and death, but the direct mechanisms beyond this phenomenon are largely unknown. Some harmful cellular events in Cystinosis might not be directly related to cystine accumulation and are the subject of our research project. Based on our previous work we hypothesized that the loss of highly specified renal cells like glomerular podocytes and renal proximal tubular cells in urine is a major mechanism causing renal pathology of Cystinosis. Increased rate of cellular abundance in urine can be explained by either the decreased adhesion of renal cells to their matrix or their increased motility or by a combination of both mechanisms. Indeed we demonstrated that both events occur in cultured human renal cells derived from Cystinosis patients. We further tried to explore the mechanisms beyond this cellular loss. It has been reported in other diseases that increased cell motility and defective adhesion can be associated with the altered protein kinase signaling. In cystinotic podocytes we found an increased expression of activated or phosphorylated Akt kinases compared to control cells. This could explain, at least partially, the abnormal phenotype. We are currently testing other protein kinases that might contribute to this mechanism. In addition we tested the gene expression of several integrin in podocytes, as podocytes adhere to the extracellular matrix using integrin receptors. Although only minor differences were found between cystinotic and control cells, cell surface expression of these proteins still has to be studied. So far most of our experiments were done in podocytes. We recently started to investigate proximal tubular epithelial cells which also showed an increased expression of phosphorylated Akt kinases unifying the concept of the hypothesis over different renal cell types. Our future plan includes also the experimentation with different kinase inhibitors to explore if they can reverse abnormal renal phenotype.

CRN Research Funding Update 2015

November 2015 Grants Awarded

The Cystinosis Research Network is pleased to announce its grant awardees for 2016. These three grants represent one established Cystinosis researcher in Dr. Levtchenko’s group in Belgium, one esteemed neuroscience lab at Montefiore in the Bronx which is expanding their work into cystinosis, and one innovative newborn screening initiative in Germany led by Dr. Hohenfellner. The grants total over $200,000 in funding for 2016. They are:

“Mechanisms Underlying Neurocognitive Changes in Cystinosis” John Foxe, PhD, Sophie Molhom, PhD, Steven U. Walkley, DVM PhD, Co-Principal Investigators Departments of Neuroscience and Pediatrics and Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY Aims for the project are to explore sensory processing and multisensory integration as potential biomarkers using high-density electrophysiological mapping techniques in individuals with Cystinosis and to determine the cell biological contributions to neuronal dysfunction in Cystinosis and their impact on neural network connectivity. Grant Year One: $98,010

“Postpartal Screening for Cystinosis with urine dipsticks at the age of 12 weeks” PD Dr. med. Katharina Hohenfellner, LÄ Kindernephrologie, Kinderklinik Traunstein, Cuno-Niggl-str.3, 83278 Traunstein, Germany Dr. med. Uta Nennstiel Ratzel MPH, Leitung Sachgebiet GE4, Präsidentin der Deutschen Gesellschaft für Screening, Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Veterinärstr.2, 85762 Oberschleißheim Prof. Dr. med. Lothar Thomas, Emeritus Direktor Laboratoriumsmedizin , Klinikum Frankfurt Höchst, 65929 Frankfurt, Germany Prof. Dr. med Erich Harms, Emeritus Direktor, Kinderklinik Münster, 48149 Münster, Germany The objective of the present study is to determine if screening with urine strips can detect patients with Cystinosis during early childhood. This study plans to test infants born in Bavaria, during the next two years, with a urine dipstick at the age of 12 weeks. If this method yields valid as a screening method for Cystinosis, we plan to integrate it into the standard German child health care examinations. Total grant: $25,000

“Altered protein kinase signaling as a cause of reduced adhesion and increased motility of renal epithelial cells in Cystinosis” E. Ivanova, L. van den Heuvel, E. Levtchenko Katholieke Universiteit Leuven, Belgium In this project, we will focus on the altered cytoskeleton and increased motility of cystinedeficient human podocytes and proximal tubular epithelial cells that may underlie the increased renal cell loss in cystinosis and the development of kidney damage. We will also further investigate the mechanisms of altered vesicular trafficking that can link disturbed endocytosis to protein kinase signalling. Finally, we will study the effects of cysteamine and various protein kinase inhibitors on the abnormal phenotype of cystinotic cells. The obtained results will contribute to the understanding of the pathogenesis of cystinosis and will help identifying novel therapeutic targets to improve the treatment of the disease. Grant Year One: $77,000

We are happy to support all three groups important work and will report results back to the community.

CRN Research Funding Update 2014

Extension of Genotype-Phenotype in Egyptian Patients with Nephropathic Cystinosis. Neveen Soliman, MD and Elena Levtchenko, MD, PhD, Center of Pediatric Nephrology and Transplantation, Cairo Univeristy, Egypt and Department of Pediatric Nephrology Univeristy Hospitals, Leuven, Belgium. Total Award: $4,400

Extension of Proteomic Investigation of Cystinotic Cells and the Effects of Cysteamine Treatment. Jill Jobson, Noel Carter, Achim Treumann, Ken McGarry and Rosaleen J. Anderson, Sunderland Pharmacy School, University of Sunderland. Total Award: $55,000

Extension of the Continuation of Feasilbility of Cystinosin Replacement Therapy in Cystinosis. Jess G. Thoene, MD, Director, Biochemical Genetics laboratory, Active Profession Emeritus of Pediatrics, University of Michigan. Total Award: $81,000

National Institutes of Health Cystinosis Fellowship, 2013 – 2015, Galina Nesterova, MD, Mentor, William A. Gahl, MD, PhD. Total Award: $130,000

CRN Research Funding Update 2013

CRN has granted new funding for three research project extensions plus an extension of the NIH Clinical Fellowship for 2013:

Rosaleen Anderson, PhD, Sunderland Pharmacy School, University of Sunderland, “Continuation of proteomic investigation of cystinotic cells and the effects of cysteamine treatment”. Total award: $54,121.23

Neveen Soliman, MD and Elena Levtchenko, MD, PhD, Center of Pediatric Nephrology and Transplantation, Cairo University, Egypt and Department of Pediatric Nephrology University Hospitals, Leuven, Belgium, “Genotype-Phenotype in Egyptian Patients with Nephropathic Cystinosis.” Total award: $20,139.00

Jess G. Thoene, MD, Director, Biochemical Genetics Laboratory, Active Professor Emeritus of Pediatrics, University of Michigan, “Extension of the Continuation of Feasibility of Cystinosin Replacement Therapy in Cystinosis.” Total award: $81,000.00

Galina Nesterova, MD, National Institutes of Health Cystinosis Fellow. Total award: $130,000.00

Ongoing projects:

Dr. C. Tuleu, University of London, School of Pharmacy, Dr. Olufemi Rabiu, Guy’s St. Thomas’ NHS Foundation Hospital, Mr. Ken K. Nischal, Mr. Rajnish Sekhri, and Dr. William Van’t Hoff, Great Ormond Street Hospital and Institute of Child Health “Development of a cysteamine in situ gelling system for the topical treatment of corneal crystals in cystinosis.” Total award:$203,500.00

Leticia Belmont, M.D., Laboratory of Inborn Errors of Metabolism and National Institute of Pediatrics, Mexico. “Determination of Intra-leucocotary Cystine by HPLC in patients with cystinosis.” Total award: $31,972.00

CRN Research Funding Update 2012

A major focus of the Cystinosis Research Network continues to be a determined effort to secure a promising future for the cystinosis community through the sup-port and funding of research grants that lead to improved treatments and ultimately a cure for cystinosis. CRN has a current research commitment of over $800,000.00 and has funded nearly $3 million total in research grants and fellowships.

Current Research Studies:

Neveen Soliman, MD and Elena Levtchenko, MD, PhD, Center of Pediatric Nephrology and Transplantation, Cairo University, Egypt and Department of Pediatric Nephrology University Hospitals, Leuven, Belgium, “Genotype-Phenotype in Egyp-tian Patients with Nephropathic Cystinosis”, Grant awarded March 2012 for a 12 month period. Total award: $15,750.

Martine Besouw, MD, Department of Women and Child Laboratory of Pediatrics, University Hospitals, Leuven Belgium, “Study of skin changes in cystinosis patients under cysteamine therapy”, Mentor: Elena Levtchenko, MD, PhD. Grant awarded 6 December 2011 for a 12 month period. Total Award: $99,400.00. This grant is a joint funding collaboration between Cystinosis Research Network and Cystinosis Foundation Ireland.

Maya Doyle, LCSW, Children’s Hospital at Montefiore, Division of Pediatric Nephrology, New York University, “Cystinosis in Emerging Adulthood”. A one-time grant awarded on 24 July 2011 for a total of $17,200.

Jess G. Thoene, M.D, Director, Biochemical Genetics Laboratory, Active Professor Emeritus of Pediatrics, University of Michigan, “Continuation of Feasibility of Cystinosin Replacement Therapy in Cystinosis”, Grant awarded 24 July 2011 for an 18 month period for $202,500.00.

Rosaleen Anderson, PhD, Sunderland Pharmacy School, University of Sunderland, “Proteomic investigation of cystinotic cells and the effects of cysteamine treatment”. Grant awarded: 23 November 2010 for a term of 2 years in the amount of GPB 80,926.00 or $130,366.00 based on the exchange rate for 15 November 2010.

Catherine Tuleu, Ph.D, Ken Nischal, Olufemi Rabiu, Rajnish Sekhri, William Van’t Hoff, Univ. of London, School of Pharmacy; “Development of cysteamine in situ gelling system for the topical treatment of corneal crystals in cystinosis”, Grant awarded January 2007 for 3 years. Total award: 103,000.00 pounds or approximately $203,500.00.

Leticia Belmont, M.D, Unidad de Genetica de la Nutrician, Instituto Nacional de Pediatria, Mexico. “Determination of Intraleucocitary Cystine by High Performance Liquid Cromatography (HPLC) in Patients with Cystinosis”. Grant Awarded: 5 November 2008 Total award: $31,972.00; A presentation, citing CRN funding, was given at the IPNA mee-ting in NYC, 31 August 2010.

Henk J. Blom, M.D., M.M.C. Wamelink, and E. Levtchenko, M.D., VU University Medi-cal Center, Amsterdam, The Netherlands: “Newborn Screening of Cystinosis”. Grant Awarded: 5 November 2008; Total Award: 45,000 euros (approximately $67,500.00.

Francisco Emma, M.D. and Anna Taranta, Ph.D., Bambino Gesu Children’s Hospital and Research Institute, Rome, Italy: “Functional Characterization of Cystinosin LKG”. Grant Awarded: 5 November 2008; Total Award: $114,480.00.

Ewa Elenberg, M.D., Texas Children’s Hospital, Houston, TX “Quality of Life in Cystinosis Patients”, Grant awarded 9-25-09 for 1 year . Total award: $21,000.00

CRN Research Funding Update 2011

CRN’s Research Committee oversees the research interests of the organization and is responsible for the strategic direction in all areas of research. An official Call for Proposals is issued once a year and researchers are encouraged to submit their requests for funding for grants that offer the promise of achieving CRN’s goals of improved treatment and a cure for cystinosis. All proposals received are reviewed by CRN’s Scientific Review Board and funds are granted based on the recommendation of the Board. The 2011 grant proposal requests were reviewed by the Scientific Review Board this past July, 2011 in conjunction with CRN’s Family Conference, and we are proud to announce that the following new grants have been awarded:

Maya Doyle, LCSW, Children’s Hospital at Montefiore, Division of Pediatric Nephrology, New York University, Cystinosis in Emerging Adulthood.. One time grant of $17,200.00 awarded July 2011; payment processed 17 August 2011. Study and payment complete.

Jess G. Thoene, M.D, Director, Biochemical Genetics Laboratory, Active Professor Emeritus of Pediatrics, University of Michigan, Continuation of Feasibility of Cystinosin Replacement Therapy in Cystinosis.. Grant awarded 24 July 2011 for an 18 month period for $202,500.00. Initial payment processed 17 August 2011.

Martine Besouw, MD, Elena Levtchenko, MD, PhD; Lambertus vanden Heuvel, PhD, Univ. Medical Center Nijmegen, The Netherlands, “Study of skin changes in cystinosis patients under cysteamine therapy.. Grant awarded October 2011 for a 12 month period for $90,400.00 Co-funded by Cystinosis Foundation Ireland.

Recently completed Research Grants:

Dr. Paul Goodyer, Montreal Children’s Hospital, Montreal, Canada, and Dr. Rick Kaskel, Children’s Hospital at Montefiore, Bronx, NY. “Proposal for a North American Cystinosis Research Platform”. One year grant of $36,000.00 awarded for development.

Jess Thoene, MD, Univ. of Michigan, Ann Arbor, Tissue Repository for Cystinosis. Grant awarded: Start date: Nov. 2006 Total award: $26,206.00. Final report recd 15 Sept 2010.

Viki Kalatzis, PhD, Eric J. Kremer, PhD, Institut Genetique Moleculaire de Montpellier, France, Gene transfer studies for cystinosis. Grant awarded 29 Aug 2007, 2 yrs. Total award: Euros 75,900.00, approx. US$104,619.48. Final report received 25 November 2009.

Jess Thoene, M.D., University of Michigan, Ann Arbor, MI, “Feasibility of Cystinosin Replacement Therapy in Cystinosis”, Grant awarded 9-25-09 for two years (9-1-09 to 8-31-11) Total Award: $165,732. Final report received August 31, 2011, Final payment of $55,247.00.

CRN Research Grants in Progress as of July, 2011:

Rosaleen Anderson, PhD, Sunderland Pharmacy School, University of Sunderland, “Proteomic investigation of cystinotic cells and the effects of cysteamine treatment”. Grant awarded: 23 November 2010 for a term of 2 years in the amount of GPB 80,926.00 or $130,366 based on the exchange rate for 15 November 2010.

Elena Levtchenko, MD, PhD Univ. Medical Center Nijmegen, The Netherlands, Study of ATP metabolism in human cystinotic proximal tubular cells and in humans with cystinosis in vivo. Grant awarded: 11 September 2006. Total award: $68,090.00 Balance remaining on grant: $17,022.50 A Final report was received on 5 February 2009. However, Dr. Levtchenko has indicated that the In vivo part of this project is not finished yet due to the technical difficulties with the MRS apparatus, but we have good hope that the problem will be solved and this part of the study will be finished in 2009..

Catherine Tuleu, PhD, Ken Nischal, Olufemi Rabiu, Rajnish Sekhri, Wm Van’t Hoff, MD Univ. of London, School of Pharmacy; Development of cysteamine in situ gelling system for the topical treatment of corneal crystals in cystinosis., Grant awarded January 2007 for 3 years. Total award: 103,000.00 pounds or approximately $203,500.00. Balance remaining on grant approximately $71,703.09.

Leticia Belmont, M.D., Unidad de Genetica de la Nutrician, Instituto Nacional de Pediatria, Mexico. Determination of Intraleucocitary Cystine by High Performance Liquid Cromatography (HPLC) in Patients with Cystinosis. Grant Awarded: 5 November 2008 Total award: $31,972.00; Balance re-maining on grant: $15,986.00. Presentation, citing CRN funding, was given at the IPNA meeting in NYC, 31 August 2010. Progress report Sept. 2010

Henk J. Blom, M.D., M.M.C. Wamelink, and E. Levtchenko, VU University Medical Center, Amsterdam, The Netherlands: Newborn Screening of Cystinosis.. Grant Awarded: 5 November 2008; Total Award: 45,000 euros (approximately $67,500.00); Balance remaining on grant: 33,750 euros

Francisco Emma, M.D. and Anna Taranta, Ph.D., Bambino Gesu Childrens Hospital and Research Institute, Rome, Italy: Functional Characterization of Cystinosin-LKG.. Grant Awarded: 5 November 2008; Total Award: $114,480.00; Balance remaining on grant: $21,465.00

Ewa Elenberg, MD, Texas Children’s Hospital, Houston, TX “Quality of Life in Cystinosis Patients”, Grant awarded 9-25-09 for 1 year . Total award: $21,000.00 Balance remain-ing on grant: $7,875.00.

CRN Funds New Research Project

Rosaleen Anderson, PhD, Sunderland Pharmacy School, University of Sunderland, “Proteomic investigation of cystinotic cells and the effects of cysteamine treatment”. Grant awarded: 23 November 2010 for a term of 2 years in the amount of GPB 80,926.00 or $130,366 based on the exchange rate for 15 November 2010.

Ongoing Research Commitments

Jess Thoene, MD, Univ. of Michigan, Ann Arbor, “Tissue Repository for Cystinosis” Grant awarded: 30 August 2005, interrupted immediately by hurricane Katrina. New start date: 21 Nov. 2006 – ongoing. Total award: $26,206.00

Elena Levtchenko, MD, PhD Univ. Medical Center Nijmegen, The Netherlands, “Study of ATP metabolism in human cystinotic proximal tubular cells and in humans with cystinosis in vivo” Grant awarded: 11 September 2006 for 1 year, Jan. 2007 thru Dec. 2007. Total award: $68,090.00. A “Final report” for this study was received 5 February 2009. However, an email from Dr. Levtchenko indicated that the “In vivo part of this project is not finished yet due to the technical difficulties with the MRS apparatus, but we have good hope that the problem will be solved and this part of the study will be finished in 2009”. CRN acknowledged receipt of this report, but has not accepted it as a “final” report. Dr. Levtchenko is now associated with the Department of Pediatric Nephrology, University Hospital, Leuven, Belgium.

Catherine Tuleu, PhD Univ. of London, School of Pharmacy (other names on grant: Ken Nischal, Olufemi Rabiu, Rajnish Sekhri, Wm Van’t Hoff and Bola Lawal) “Development of cysteamine in situ gelling system for the topical treatment of corneal crystals in cystinosis”, Agreement signed 24 Oct. 2006; Grant awarded January 2007 for 3 years, 1 Mar 2007 – Feb. 2010.

Leticia Belmont, M.D., Unidad de Genetica de la Nutrician, Instituto Nacional de Pediatria, Mexico. “Determination of Intraleucocitary Cystine by High Performance Liquid Cromatography (HPLC) in Patients with Cystinosis”. Grant Awarded: 5 November 2008 for 1 year (Fall ’08 – Fall ’09) Total award: $31,972.00.

Henk J. Blom, M.D., M.M.C. Wamelink, and E. Levtchenko, VU University Medical Center, Amsterdam, The Netherlands: “Newborn Screening of Cystinosis”. Grant Awarded: 5 November 2008 for 18 months (Fall 2008 – Spring 2010). Total Award: 45,000 euros (approximately $67,500.00 — approximately 60,818.71 USD, as calculated 3-2010).

Francisco Emma, M.D. and Anna Taranta, Ph.D., Bambino Gesu Children’s Hospital and Research Institute, Rome, Italy: “Functional Characterization of Cystinosin-LKG”. Grant Awarded: 5 November 2008 for 2 years (January 2009 – December 2010). Total Award: $114,480.00.

Jess Thoene, M.D., University of Michigan, Ann Arbor, MI, “Feasibility of Cystinosin Replacement Therapy in Cystinosis”, Grant awarded 9-25-09 for two years (9-1-09 to 8-31-11) Total Award: $165,732.00.

Dr. Ewa Elenberg, Texas Children’s Hospital, Houston, TX “Quality of Life in Cystinosis Patients”, Grant awarded 9-25-09 for 1 year (10-1-09 to 9-30-10) Total award: $21,000.00. Dr. Paul Goodyer, Montreal Children’s Hospital, Montreal, Canada, and Dr. Rick Kaskel, Children’s Hospital at Montefiore, Bronx, NY. “Proposal for a North American Cystinosis Research Platform”. One year grant of $36,000.00 awarded for development.

CRN Funds 3 New Research Projects

September 29, 2009
The Cystinosis Research Network is happy to announce that it will provide funding for three new research projects as a result of it’s 2009 Call for Proposals. These studies represent an additional $250,000 in research funding, putting CRN’s current research funding commitment at $1.3 million dollars. The three new projects funded are: “Feasibility of Cystinosin Replacement Therapy in Cystinosis”, Dr. Jess Thoene, University of Michigan, Ann Arbor, MI “Quality of Life in Cystinosis Patients”, Dr. Ewa Elenberg, Texas Children’s Hospital, Houston, TX “Proposal for a North American Cystinosis Research Platform”, Dr. Paul Goodyer, Montreal Children’s Hospital, Montreal, Canada, and Dr. Rick Kaskel, Children’s Hospital at Montefiore, Bronx, NY We welcome Dr. Elenberg, Dr. Kaskel, and Dr. Goodyer as new CRN funded investigators, and we look forward to our continued relationship with Dr. Thoene. We also wish to thank the CRN Scientific Review Board for their thoughtful review and recommendations regarding this years’ submitted proposals.

CRN Grants $250,000 In New Research Funding

The Cystinosis Research Network’s vision is the discovery of improved treatments and ultimately a cure for cystinosis. With that thought in mind, CRN issued our annual Call for Research Proposals in the Spring of 2008; and, it is with great pleasure that we can now present to you the latest additions to CRN’s research team, totaling nearly $250,000 in new research funding! CRN and the cystinosis community are so very fortunate to have the experience and expertise of these dedicated researchers included in our pursuit of a better life for the cystinosis patient.

Leticia Belmont Martinez, M.D., Unidad de Genetica de la Nutricion, Instituto Nacional de Pediatria, Mexico. “Determination of Intraleucocitary Cystine by High Performance Liquid Cromatography (HPLC) in Patients with Cystinosis”; one year study; total grant: $31,972.00.

Henk J. Blom, M.D. et al, VU University Medical Center, Amsterdam, The Netherlands. “Newborn Screening of Cystinosis”; 18 month study; total grant: 45,000 euros, approximately $67,500.00

Francisco Emma, M.D. and Anna Taranta, Ph.D., Bambino Gesu Children’s Hospital and Research Institute, Rome, Italy. “Functional Characterization of Cystinosin-LKG”; 2 year study; total grant: $114,480.00.

CRN is very proud to welcome these new researchers! They join that unique group of professionals who have been involved in past and on-going research studies funded by CRN. It is because of the dedication and perseverance of all these researchers that so much progress has been made in the treatment and improved outlook for our cystinosis patients

The addition of these research grants brings CRN’s current research commitment to a total of nearly $1,000,000! It because of your continued support, and that of the cystinosis community through contributions and fundraisers, that CRN can make this research possible.