Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another.

Keywords: ADPKD; dietary intervention; mTOR; pharmacological intervention; polycystic kidney disease.

FIGURE 1

Targeted metabolic regulation in ADPKD. A highly simplified cartoon of some of the major pathways that relate to the pathogenesis of PKD and that are are affected by some of the compounds discussed in this article. Rosiglitazone treatment activates PPAR-γ, causing heterodimeric binding to retinoid x receptor (RXR) followed by translocation to the nucleus, activating gene transcription of PPAR response element-regulated genes. This in turn leads to a decrease in TGF-β signaling and a subsequent reduction in fibrosis. Rosiglitazone also acts independently of PPAR-γ to inhibit p70S6K activation and ribosomal protein S6 phosphorylation. Treatment with 2DG leads to a reduction in glycolysis by inhibition of phosphoglucoisomerase. Decreased glycolytic activity in turn may cause the activation of AMPK and subsequent inhibition of mTORC1, cell growth and proliferation with an increase in fatty acid oxidation. Metformin activates AMPK that directly represses mTORC1 signaling via phosphorylation. Treatment with BPTES inhibits glutaminase (GLS1) disrupting the breakdown of glutamine to glutamate preventing it from being used in the TCA cycle to produce α-ketoglutarate. Fenofibrate treatment activates PPAR-α to bind to PPAR response elements and increase transcription of genes involved in fatty acid utilization, oxidative phosphorylation and mitochondrial biogenesis. Rapamycin inhibits the ability of mTORC1 to activate the S6-Kinase branch of its downstream pathway but has less effect on the 4E-BP1 branch. In contrast, mTOR kinase inhibitors or mTOR ASOs would affect both downstream branches. Dietary restriction simulates the effects of targeted drug therapies by reducing nutrient intake, leading to reductions in key regulatory pathways. Pointed arrowheads indicate activating effects. Blunt arrowheads indicate inhibitory effects. Dashed arrows indicate indirect or multistep effects.

FIGURE 2

Drug targeting to renal cyst lumens in PKD. (A) Cartoon of a cross-section of a renal cyst in PKD that is lined by a single-layer epithelium forming an enclosed space. The kinase mTOR is depicted as an example of an intracellular pharmacological target that can be reached via folate-conjugated small molecule drugs as shown in (B). The cyst lumen contains growth factors and cytokines that activate receptors on the apical plasma membranes of the cyst-lining cells. These growth factors and their receptors receptors are the intended targets of antagonistic mAbs in dIgA format as shown in (C). (B) Magnified cartoon. A depiction of a folate-conjugated small molecule drug consisting of the ligand folate (1), a hydrophilic spacer (2), a cleavable bond (3) and the payload (4), which could be rapamycin in the case of FC-rapa. FC-rapa binds to the FR on the plasma membrane of cyst-lining cells and is internalized via receptor-mediated endocytosis, followed by cleavage and release of the drug in the endosome. The free, activated drug is subsequently released into the cytoplasm where it can inhibit its intended target mTOR. The FR is subsequently recycled back to the plasma membrane for additional rounds of drug uptake. Whereas cysts in PKD express the FR, most other cells instead utilize the reduced folate carrier (RFC) for folate uptake. Because the RFC cannot transport folate-conjugated drugs, these cells will be unaffected. (C) An antagonistic antibody in dIgA format (red) binds to the pIgR (green) on the basolateral surface of cyst-lining cells and is transcytosed to the apical surface. After arrival at the apical surface, the pIgR is cleaved which leads to the release of the complex between dIgA and the ectodomain of the pIgR (secretory IgA) into the cyst fluid. The dIgA antibody can then inhibit its intended target such as a growth factor or growth factor receptor (blue). Because renal cysts have enclosed spaces, the dIgA antibody will accumulate in the cyst fluid. In contrast, pIgR-mediated transcytosis will lead to excretion and loss of the dIgA antibody in other epithelial tissues such as the intestinal epithelium.