Antisense oligonucleotides ameliorate kidney dysfunction in podocyte-specific APOL1 risk variant mice
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Journal Volume
30
Journal Issue
7
Pages
2491
Date Issued
2022-07-06
Author(s)
Poudel, Bibek
Frederick, Julia
Dhillon, Poonam
Shrestha, Rojesh
Ma, Ziyuan
Wu, Junnan
Okamoto, Koji
Kopp, Jeffrey B
Booten, Sheri L
Gattis, Danielle
Watt, Andrew T
Palmer, Matthew
Aghajan, Mariam
Susztak, Katalin
Abstract
Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.
Subjects
APOL1; ASO; CKD; drug therapy; genetic diseases; nephrology
SDGs
Publisher
CELL PRESS
Type
journal article