| Authors |
Huang Y, Xing H, Osouli A, Guay-Woodford L, Chung EJ
|
| Submitted By |
Eun Ji Chung on 2/20/2026 |
| Status |
Published |
| Journal |
Journal of biomedical materials research. Part A, REFERENCES |
| Year |
2026 |
| Date Published |
|
| Volume : Pages |
114 : e70047 |
| PubMed Reference |
41656524 |
| Abstract |
Autosomal recessive polycystic kidney disease (ARPKD) is a severe inherited
disorder caused primarily by mutations in PKHD1 and in a minority of cases,
CYS1. These genes encode fibrocystin and cystin, respectively. ARPKD typically
manifests in infancy with enlarged kidneys, progressive cyst formation, and an
estimated peri-natal high mortality rate of 20%. Given the lack of efficient
therapies and the genetic complexity of many rare diseases such as ARPKD,
strategies that restore functional proteins defective in the disease may offer a
disease-modifying approach. Urinary extracellular vesicles (uEVs) are naturally
secreted by renal and urinary tract cells and contain functional kidney
proteins, including fibrocystin and cystin. As such, uEVs may be capable of
supplementing these missing proteins and delivering them directly to diseased
cells in ARPKD. To investigate the therapeutic potential of uEVs for ARPKD, we
first isolated and characterized uEVs from healthy mouse urine by nanoparticle
tracking analysis (NTA), transmission electron microscopy (TEM), and Western
blotting for EV markers. PCR confirmed the presence of Cys1 and Pkhd1 mRNAs in
uEVs, while cellular uptake was verified by fluorescence microscopy and flow
cytometry in collecting duct epithelial cells (mpkCCDc14). In vitro, uEV
treatment enhanced Cys1 and Pkhd1 levels in healthy cells, and rescued Cys1
levels in Cys1-deficient cells, derived from Cys1cpk/cpk (cpk) mice. Upon
administration in the cpk mouse model of ARPKD, uEV improved the survival rate
in cpk mice. Furthermore, in utero administration of uEVs demonstrated
accumulation in the fetal kidney and enhanced Cys1 level following
intra-amniotic (IA) administration, highlighting the feasibility of prenatal
therapy for the most severe cases of ARPKD that are lethal in utero or within
the first 24-48?h after birth. Taken together, our findings reveal that uEVs
represent a promising therapeutic modality for ARPKD, capable of restoring
deficient CYS1 protein levels and mitigating disease progression.
|
|
|