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COMPLETED

NCT07903909

Effect of Cholecalciferol on Mucin-1 Levels in Urinary Extracelllular Vesicles in Individuals With Autosomal Dominant Tubulo-Interstitial Kidney Disease Due to MUC1 Mutations (ADTKD-MUC1)

Sponsor: Gregory Papagregoriou

View on ClinicalTrials.gov

Summary

Autosomal dominant tubulointerstitial kidney disease due to MUC1 mutations (ADTKD-MUC1) is caused by mutations in the MUC1 gene encoding the protein mucin-1. The most frequently reported mutation is a cytosine insertion causing a frameshift and resulting in the production of an abnormal protein (MUC1-fs). The primary characteristic of ADTKD-MUC1 is slowly progressive chronic kidney disease, with age-dependent progression to end-stage kidney disease (ESKD). Although mucin-1 is expressed in numerous epithelial tissues, including sebaceous glands, the respiratory tract, mammary glands, and gastrointestinal tract, ADTKD-MUC1 is not typically associated with clinical manifestations outside the kidney. The Pafos region of Cyprus is home to one of the largest reported cohorts of patients with ADTKD-MUC1 worldwide, with an estimated prevalence of the MUC1 cytosine insertion of approximately 1 in 580 individuals. The chromosomal region at 1q22 associated with the disease was initially identified by investigators in Cyprus, and the Cypriot cohort has subsequently been extensively characterized and followed longitudinally. ADTKD-MUC1 currently has no approved disease-specific treatment, and most affected individuals eventually develop ESKD requiring kidney replacement therapy, at an average age of approximately 50 years. Intracellular accumulation of MUC1-fs is considered a major contributor to the pathogenesis of ADTKD-MUC1. Researchers at the Broad Institute, Harvard Medical School, and Massachusetts Institute of Technology developed a high-content screening (HCS) platform using a cell-based immunofluorescence assay to evaluate the effects of approximately 4,500 compounds from the Broad Institute drug repurposing library on patient-derived primary cells. The library included compounds at various stages of preclinical and clinical development, including FDA-approved drugs and supplements. Cholecalciferol (vitamin D3) was identified as a compound capable of reducing both wild-type mucin-1 (MUC1) and frameshift mucin-1 (MUC1-fs) protein levels in vitro, as demonstrated by immunofluorescence experiments. Based on these preliminary findings, the investigators hypothesize that administration of a single high dose of cholecalciferol to patients with ADTKD-MUC1 may reproduce the reduction in MUC1-fs protein levels observed in vitro. Cholecalciferol (vitamin D3) is commonly used for the prevention and treatment of vitamin D deficiency. The study therefore aims to investigate the effects of cholecalciferol administration on MUC1 and MUC1-fs protein levels in urinary extracellular vesicles collected from Cypriot patients with genetically confirmed ADTKD-MUC1 carrying the MUC1 cytosine insertion mutation.

Official title: Open-Label, Single-Arm Pilot Study of the Effect of Cholecalciferol on Mucin-1 Levels in Individuals With Autosomal Dominant Tubulo-Interstitial Kidney Disease Due to MUC1 Mutations (ADTKD-MUC1)

Key Details

Gender

All

Age Range

18 Years - 75 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2019-09-06

Completion Date

2026-01-01

Last Updated

2026-10-29

Healthy Volunteers

Yes

Conditions

Tubulointerstitial Kidney Diseases MUC1 Kidney Disease

Interventions

DIETARY_SUPPLEMENT

Cholecalciferol (Vit D3)

Brand: Health Aid - Vitamin D3 50.000 IU caps Dose: 4 x 50.000 IU orally, once.

Inclusion Criteria: 1. Ages between 18-75 years 2. Prior established genetic diagnosis of ADTKD-MUC1. Participants must be genotyped positive for the C-insertion mutation in MUC1. 3. Must have estimated glomerular filtration rate \>30 ml/min/1.73 m2 (according to the modified MDRD formula) due to ADTKD-MUC1. 4. No other serious health conditions 5. If female and of childbearing potential (premenopausal and not surgically sterile) must have a negative urine pregnancy test at the screening visit (Day -20) and be willing to use contraception from the time of the screening visit to 2 weeks following study supplement administration. Acceptable methods of birth control include abstinence, barrier methods, hormones, or an intra-uterine device. 6. Able to understand and comply with requirements of the entire study and to communicate with the study team. 7. The patient has not taken cholecalciferol, ergocalciferol or other Vitamin D related supplements in the month prior to study initiation. 8. Participants agree NOT to take ergocalciferol or cholecalciferol (except for \<500 IU that is contained in a daily multi-vitamin) for one month after receiving the one-time dose of cholecalciferol. 9. Written informed consent using a document that has been approved by the Cyprus National Bioethics Committee. Exclusion Criteria: 1. Manifestation of a major systemic illness, other than chronic kidney disease. Specifically, history of granulomatous disorders (sarcoidosis, tuberculosis), hyperparathyroidism or other disorders of calcium metabolism. 2. A history of nephrolithiasis. 3. A history of osteoporosis or osteopenia. 4. A fracture or a fall that did not occur during exercise within the last six months. 5. Intolerance or known allergic reaction to cholecalciferol or Vitamin D in general. 6. Estimated glomerular filtration rate \< 30 ml/min/1.73 m2 or s/p kidney transplantation 7. 25 hydroxy Vitamin D level \> upper limit of normal. 8. Pregnancy. 9. Lactating. 10. Hepatic disease. 11. Receiving glucocorticoids. 12. Excluded medications: The participant cannot be receiving \> 1000 mcg oral cholecalciferol. The participant cannot be receiving ergocalciferol, calcitriol, or other vitamin D analogs. The participant cannot be receiving any medications for the treatment of osteoporosis. Participants must refrain from taking cholecalciferol or ergocalciferol except for doses \<500 IU included in daily vitamins, for one month after Day 0.

Locations (1)

Evangelismos Private Hospital

Paphos, Cyprus