Messenger RNA (
mRNA)
therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in
cystinosis using synthetic
mRNA in cell models and ctns-/- zebrafish embryos.
Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal
cystine-H+
symporter cystinosin, and leading to
cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage
kidney failure. The current therapeutic standard
cysteamine, reduces
cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic
mRNA can restore lysosomal cystinosin expression following lipofection into CTNS-/- kidney cells and injection into ctns-/- zebrafish. A single CTNS
mRNA administration decreases cellular
cystine accumulation for up to 14 days in vitro. In the ctns-/- zebrafish, CTNS
mRNA therapy improves proximal tubular reabsorption, reduces
proteinuria, and restores brush border expression of the multi-
ligand receptor
megalin. Therefore, this proof-of-principle study takes the first steps in establishing an
mRNA-based
therapy to restore cystinosin expression, resulting in
cystine reduction in vitro and in the ctns-/- larvae, and restoration of the zebrafish pronephros function.