Fo006the Nrf2 Activator Bardoxolone Methyl Inhibits Cyst Formation, Reduces Inflammation, and Improves Mitochondrial Function in Cellular Models of Polycystic Kidney Disease

Miller, Greg; Isaac, Treviño; Lyndsey, McCauley; Hannigan, Linda; Probst, Brandon L.; Ferguson, Deborah; Wigley, Christian

doi:10.1093/ndt/gfz096.fo006

Cited by 2 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to tolvaptan, other drug candidates have shown promising therapeutic efficacy in preclinical studies, but enthusiasm was dampened during clinical trials due to severe side effects. For example, although bardoxolone methyl, a Nrf2 pathway activator that restores mitochondrial function and inhibits pro-inflammatory signals, showed benefits in reducing cystogenesis in ADPKD cell lines [13], bardoxolone methyl induced cardiac and gastrointestinal disorders in clinical trials [14]. Metformin (met), an AMPK activator and mTOR inhibitor, currently FDA approved for diabetes, was found to slow disease progression in recent phase 2 clinical trials in ADPKD patients [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Huang

Wang

Chin

et al. 2022

Preprint

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a variety of candidate drugs have been found to modulate cystogenesis in animal studies, results from clinical trials have often been unfavorable due to low renal bioavailability and drug-induced side effects. To mitigate this, nanoparticles can be designed to deliver drugs directly to the target organ to increase effective dose while limiting off-target side effects. Unfortunately, there are no kidney-targeted nanomedicines clinically available, and most of the existing FDA-approved nanoparticles require intravenous administration which is not suitable for ADPKD that require lifelong therapy. To address this, we developed an oral drug delivery system using chitosan nanoparticles (CS-NP) that were loaded with peptide amphiphile micelles carrying metformin (met), an ADPKD drug candidate (CS-KM-met). We previously showed that CS-NP can shield met in the gastrointestinal tract; thus, we hypothesized that CS-NP could also enhance bioavailability of kidney-targeting micelles (KMs) upon oral administration. Specifically, we measured the loading capacity of KM-met in CS-NP, evaluated the stability of CS-KM-met under acidic conditions that mimic the gastric environment, and measuredin vitrotherapeutic effects. Upon oral administration in C57BL/6J mice, CS-KM-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM-met without CS-NP or free met for up to 24 hours. As such, CS-KM-met treatment in PKD mice (Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre) which develops PKD over the course of 120 days and mimics the chronic and slowly developing nature of the human disease, showed enhanced therapeutic efficacy without affecting safety despite repeated treatment. Herein, we demonstrate the potential of CS-KM as a nanomedicine strategy for oral delivery for the long-term treatment of chronic kidney diseases such as ADPKD for the first time.

show abstract

Section: Introductionmentioning

confidence: 99%

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Huang

Wang

Chin

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to tolvaptan, other drug candidates have shown therapeutic promise in preclinical studies; however, similar to tolvaptan, enthusiasm was dampened during clinical trials due to severe side effects. For example, bardoxolone methyl, which restores mitochondrial function, inhibits inflammation, and showed benefits in reducing cystogenesis in ADPKD cells ( 13 ), induced cardiac and gastrointestinal disorders and led to early clinical trial discontinuation ( 14 ). Additionally, although metformin, an AMPK activator and mTOR inhibitor that is currently FDA approved for diabetes, was found to significantly inhibit disease progression in PKD mice ( 15 ), clinical trials testing metformin in ADPKD patients only slightly reduced the glomerular filtration rate decline ( 16 ) and caused hypoglycemia and lactic acidosis ( 17–19 ).…”

Section: Introductionmentioning

confidence: 99%

Oral delivery of nanomedicine for genetic kidney disease

Huang,

Wang,

Mancino

et al. 2024

PNAS Nexus

View full text Add to dashboard Cite

Chronic and genetic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) have few therapeutic options, and clinical trials testing small molecule drugs have been unfavorable due to low kidney bioavailability and adverse side effects. Although nanoparticles can be designed to deliver drugs directly to the diseased site, there are no kidney-targeted nanomedicines clinically available, and most FDA-approved nanoparticles are administered intravenously which is not ideal for chronic diseases. To meet these challenges of chronic diseases, we developed a biomaterials-based strategy using chitosan particles (CP) for oral delivery of therapeutic, kidney-targeting peptide amphiphile micelles (KMs). We hypothesized that encapsuling KMs into CP would enhance the bioavailability of KMs upon oral administration given the high stability of chitosan in acidic conditions and mucoadhesive properties enabling absorption within the intestines. To test this, we evaluated the mechanism of KM access to the kidneys via intravital imaging and investigated the KM biodistribution in a porcine model. Next, we loaded KMs carrying the ADPKD drug metformin into CP (KM-CP-met) and measured in vitro therapeutic effect. Upon oral administration in vivo, KM-CP-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM only or free drug. As such, KM-CP-met treatment in ADPKD mice (Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre which develops the disease over 120 days and mimics the slow development of ADPKD) showed enhanced therapeutic efficacy without affecting safety despite repeated treatment. Herein, we demonstrate the potential of KM-CP as a nanomedicine strategy for oral delivery for the long-term treatment of chronic kidney diseases.

show abstract

Fo006the Nrf2 Activator Bardoxolone Methyl Inhibits Cyst Formation, Reduces Inflammation, and Improves Mitochondrial Function in Cellular Models of Polycystic Kidney Disease

Cited by 2 publications

References 0 publications

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Oral delivery of nanomedicine for genetic kidney disease

Contact Info

Product

Resources

About