Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations

Nastaran Daneshgar; Peir-In Liang; Renny S Lan; McKenna M Horstmann; Lindsay Pack; Gourav Bhardwaj; Christie M Penniman; Brian T O'Neill; Dao-Fu Dai

doi:10.1016/j.kint.2021.12.006

Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations

Kidney Int. 2022 May;101(5):906-911. doi: 10.1016/j.kint.2021.12.006. Epub 2021 Dec 22.

Authors

Nastaran Daneshgar¹, Peir-In Liang², Renny S Lan³, McKenna M Horstmann¹, Lindsay Pack⁴, Gourav Bhardwaj⁵, Christie M Penniman⁵, Brian T O'Neill⁶, Dao-Fu Dai⁷

Affiliations

¹ Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
² Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
⁴ Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
⁵ Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁶ Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Veterans Affairs Health Care System, Iowa City, Iowa, USA.
⁷ Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. Electronic address: dao-fu-dai@uiowa.edu.

Abstract

Pregnancy is proposed to aggravate cyst progression in autosomal dominant polycystic kidney disease (ADPKD) but Tolvaptan, the only FDA-approved drug for adult ADPKD, is not recommended for pregnant ADPKD patients because of potential fetal harm. Since pregnancy itself may increase the risk for ADPKD progression, we investigated the safety and efficacy of Elamipretide, a mitochondrial-protective tetrapeptide. Elamipretide was found to ameliorate the progression of kidney disease in pregnant Pkd1^RC/RC mice, in parallel with attenuation of ERK1/2 phosphorylation and improvement of mitochondrial supercomplex formation. Furthermore, Elamipretide was found to pass through the placenta and breast milk and ameliorate aggressive infantile polycystic kidney disease without any observed teratogenic or harmful effect. Elamipretide has an excellent safety profile and is currently tested in multiple phase II and phase III clinical trials. These preclinical studies support a potential clinical trial of Elamipretide for the treatment of ADPKD, particularly for patients that cannot take Tolvaptan.

Keywords: elamipretide; mitochondria; polycystic kidney disease; pregnancy.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Female
Humans
Male
Mice
Mutation
Oligopeptides
Polycystic Kidney Diseases* / drug therapy
Polycystic Kidney, Autosomal Dominant* / drug therapy
Polycystic Kidney, Autosomal Dominant* / genetics
Pregnancy
Tolvaptan / therapeutic use

Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations

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