We’ve developed a new way of reducing cyst growth and preserving kidney and liver function in both AD- and ARPKD, using CFTR modulators such as VX-809, already approved by the FDA to treat patients with Cystic Fibrosis.  In both rapid onset and slowly progressing mouse models of ADPKD, VX-809 reduced cyst growth, improved renal function and reduced proliferation.  We found in cell models that treatment with VX-809 of both kidney cysts in ADPKD and liver cysts in ARPKD caused CFTR’s colocalization to change from its cystic location consistent with secretion to a basolateral location consistent with fluid absorption.  In the cell models of AD- and ARPKD, trafficking, degradative and signaling pathways were altered fueling cyst growth; and restored toward normal by VX-809.  Thus, VX-809 and potentially other CFTR modulators could be powerful treatment options to reduce cyst growth and restore renal function in both AD- and ARPKD.

Bardoxolone methyl (Bard), an Nrf2 activator, improved kidney function (eGFR) in previous clinical trials that enrolled over 3,000 patients with various forms of chronic kidney disease. A Phase 2 study showed Bard increased mean eGFR by 9.3 ± 1.4 mL/min/1.73 m2 in subjects with ADPKD after 12 weeks of treatment in a patient population with a historical eGFR decline of ~4.8 mL/min/1.73 m2 annually. Additionally, Bard was well-tolerated with no patients reporting serious adverse events. As a result, a Phase 3 trial (FALCON; NCT03918447) was designed to further assess the safety, tolerability, and efficacy of Bard on rate of decline in eGFR in subjects with ADPKD. FALCON is enrolling 550 subjects with ADPKD, aged 18 to 70 years, eGFR ≥ 30 ≤ 90 mL/min/1.73 m2, and UACR ≤ 2500 mg/g. Enrolled subjects will continue treatment until Week 100 and will be followed for an additional 4 weeks off study drug.

Brain aneurysms (ICA) are dilatation of the brain vessels that are prone to rupture, leading to bleeding within the brain and a mortality rate up to 50%. ICA occur more frequently in patients with ADPKD than in the general population with an average age of 39 years at rupture. Risk factors for ICA rupture in ADPKD include a family history of brain bleeding or aneurysm. Almost all cases of ruptured ICA have been reported in adult patients, and it is extremely rare in pediatrics. Here, we report a case of a 9-year-old boy who presented with a ruptured ICA preceding his ADPKD diagnosis. Although he has a strong family history of ADPKD, there was no history of ICA or bleeding. This report is important to raise awareness that ICA rupture can occur in children with ADPKD with a negative family history of ICA.

We examined how ADPKD patients fair in comparison with patients with other cystic kidney disease or cystic liver disease after being tested COVID-19 positive in the VA health system. Our results from 318 ADPKD patients that were confirmed COVID-19 positive showed that ADPKD is not an independent contributor to severe COVID-19 illness outcomes (hospitalization, ICU admission, ventilator requirement, and mortality). However, ADPKD is significantly associated with increased risk for new post-COVID-19 dialysis incidences.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and the 4th common cause for renal replacement therapy worldwide. ADPKD is characterized by the development of multiple renal cysts in both kidneys progressively leading to end-stage kidney disease by the age of 60 years. If ADPKD has been historically considered as an “adult-onset” disease, it is now recognized that the adult expression of the disease is only the tip of the iceberg, while cyst formation already begins in utero and a significant proportion of children displayed symptoms during childhood.

The ADPedKD Registry is a secured international worldwide web-based database that includes longitudinal data from young ADPKD patients (≤19 years). The aim of this registry is to give insights in the pediatric manifestations of the disease. Hereby, we report some data from the ADPedKD registry focusing on the basic’s characteristics of patients, reason for diagnosis and main clinical manifestations.

Polycystic kidney and liver diseases belong to a family of genetic fibrocystic disorders that primarily affect the kidney and liver. In previous work, we have shown that XBP1 (a critical component of the unfolded protein response) and SEC63 (one of the Autosomal Dominant Polycystic Liver Disease, ADPLD, genes) interact genetically to control the severity of the polycystic phenotype in a polycystin-1-dependent (encoded by Pkd1, one of the two ADPKD genes) manner.
In the current project we have examined the impact of XBP1 on the progression of cystic disease due to Pkd1 missense mutations. We have found that activation of XBP1 in vitro and in vivo leads to improved PC1 biogenesis and decreased severity of cystic disease. Our study sheds light on a potentially important approach to tackle polycystic kidney disease in a mutation specific fashion and may form the basis of future personalized interventions for ADPKD patients.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the fourth leading cause of end stage renal disease. Although tolvaptan has been recently approved by FDA for ADPKD, but several adverse effects of this drug make it unsuitable for many patients. Therefore, development of novel therapies against this cystic disease is of great importance. Nutritional manipulations studies involving a decrease in food intake or time restricted feeding have shown beneficial effects in animal models of PKD. Despite the fact that these nutritional manipulations are effective treatments, they do have many limitations. In the present study, we show that dietary restriction of methionine has beneficial effects in animal model of PKD. Thus, dietary interventions involving MR have great potential as an alternative nutritional therapeutic strategy against this cystic disease.

One of the first defects that leads to the formation of cysts in polycystic kidney disease (PKD) is an abnormally low level of calcium inside the kidney cells. In healthy individuals, polycystin-2 (PC2) allows calcium entry into kidney cells, and about 85% of PKD cases do not involve defects in PC2. A novel, PKD specific approach to restoring cellular calcium would be to identify a drug that activates PC2. We have found such a drug: pregnenolone sulfate. The drug raises the calcium level in cultured kidney cells from mice and humans. The drug reduces cysts in an assay using cultured kidney cells from mice, and it reduces cysts in an assay using cultured, whole kidneys from mice. We are confirming these studies, extending them to other models of PKD, and exploring the drug’s mechanism of action.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 genes, which results in kidney cyst formation. Here we report the evaluation of RGLS4326, a novel investigational drug identified to inhibit a target called miR-17, and to slow down kidney cyst growth. We have shown that miR-17 is overproduced in kidneys of ADPKD patients and causes decreased levels of PC1 and PC2 (proteins encoded by PKD1 and PKD2). In studies in animals with PKD, RGLS4326 increased levels of PC1 and PC2, reduced kidney injury marker uNGAL, and inhibited kidney cyst growth. In an ongoing Phase 1b study in patients with ADPKD, four doses of subcutaneous (s.c.) injections every other week of RGLS4326 in the first cohort was well tolerated and showed increases in urinary PC1 and PC2 levels. The study is continuing to enroll ADPKD patients in additional cohorts to evaluate different doses of RGLS4326.

Additional treatments for ADPKD patients to slow the progression of kidney function decline are needed. Tolvaptan, the only approved therapy, is associated with liver side effects in some patients. Lixivaptan, which works through the same mechanism as tolvaptan, has been shown in models to be potentially safer for the liver. We present here the planned Phase 3 clinical trial to show the efficacy and safety of lixivaptan. In this trial, after increasing the dose to the highest tolerated level, participants will be randomized in a ratio of 2 to 1 to receive double-blind treatment with lixivaptan or placebo for 1 year. After the first year, all participants will receive lixivaptan for the second year. The change in estimated glomerular filtration rate is the main efficacy endpoint and the increase in liver enzyme levels is the main safety endpoint. The trial is planned to start in early 2021.

About 80-85% of Autosomal Dominant Polycystic Kidney Disease (ADPKD) cases are caused by genetic mutations in the PKD1 gene, leading to production of defective Polycystin-1 (PC1) protein. PC1 is a large transmembrane protein that undergoes cleavage at its N and C-terminal domains. Cleavage at the C-terminal domain leads to the generation of PC1 C-terminal tail fragments (PC1-CTT) of approximately 17 and 34kD that are capable of translocating to the mitochondria and nucleus.

In this study we aimed to assess the effects of re-expressing the PC1-CTT in an inducible PC1 KO ADPKD mouse model. To this purpose, we first generated a BAC transgenic mouse model expressing a Flox-Stop 2HA-PC1-CTT inserted in the Rosa26 locus and crossed it with the inducible Pax8rtTA; TetO-Cre; Pkd1fl/fl ADPKD mouse model. Induction of this second-generation mouse model (PC1-CTT; Pax8rtTA; TetO-Cre; Pkd1fl/fl on the C57BL6N mouse strain background) with oral doxycycline from P28-P42 leads to re-expression of PC1-CTT in an ADPKD animal model that lacks full-length PC1. We show that expression of the PC1-CTT in this background produces dramatic effects on the cystic phenotype: PC1 KO mice that re-express PC1-CTT present a 2.5-fold decrease in kidney weight/body weight ratio (5.1% versus 13.1%, p=0.0006) and a 3.5-fold decrease in BUN (32.7mg/dL versus 109.9mg/dL, p=0.004) when compared to PC1 KO only mice.

Furthermore, we show that the BUN levels observed in these PC1-CTT expressing ADPKD mice are not significantly different from the levels observed in healthy wild-type (WT) control mice. Additionally, we show that this rescue of renal phenotype is related to a protein interaction between the PC1-CTT and the enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). NNT is a mitochondrial detoxifying enzyme that is capable of modulating intracellular Redox homeostasis by using the mitochondrial proton gradient to catalyze the following reaction: NADH+NADP+<-> NAD++NADPH. We initially identified an interaction between full-length PC1 and NNT through mass spectrometry analysis and the interaction between PC1-CTT and NNT was confirmed by coimmunoprecipitation. We assessed the relevance of this protein interaction in terms of disease progression by crossing the same PC1-CTT; Pax8rtTA; TetO-Cre; Pkd1fl/fl mice with NNT-mutant C57BL6J mice, that differ from C57BL6N because of a deletion on the NNT gene resulting in the complete lack of NNT protein. We show that these animals do not exhibit an improved cystic phenotype as a consequence of PC1-CTT expression.

Moreover, we assess the degree of Redox imbalance between NAD+/NADH in in vitro and in animal ADPKD models and show that these PC1 KO models exhibit a 50% decrease in the NAD+/NADH ratio as compared to WT models. Furthermore, while the presence of functioning NNT is associated with increased NAD+/NADH in WT C57BL6N compared to C57BL6J, the presence of this protein and the consequent Redox modulation is not sufficient to rescue disease phenotype in the absence of PC1-CTT re-expression in the PC1 KO mice.

Finally, we conclude that the significant improvement in phenotype and the small size of the PC1-CTT protein fragment and its corresponding genetic sequence could potentially open the door for effective gene therapy for ADPKD.

Autosomal Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by the growth of numerous cysts in the kidney. Currently, ADPKD is a leading cause of renal failure. Yet, we are at a paucity of successful therapeutic options.

Here, we have identified that a novel biochemical pathway called m6A-RNA methylation, is elevated in mouse and human ADPKD. The driver of this pathway, an enzyme named Mettl3 is also elevated, surprisingly, from a very early time point. Genetic hyper-activation of Mettl3 promotes cysts. Importantly, removing Mettl3 slows ADPKD and prolongs survival of ADPKD mice. The amino acid methionine is essential for Mettl3 activity. Interestingly, methionine is also increased in PKD and activates Mettl3. Importantly, methionine restriction in mouse diet slows their ADPKD progression. Finally, methionine restriction causes Mettl3 mediated inhibition of c-Myc and cAMP pathogenic signaling.

In conclusion, the methionine/Mettl3 pathway is an Achilles’ heel in ADPKD.

Tolvaptan is the only approved pharmacologic therapy for the treatment of ADPKD patients; however, it is associated with potentially serious liver side effects. Lixivaptan is a treatment under investigation for ADPKD patients similar to tolvaptan but thought to have less liver side effects based on models used to predict the liver side effects of drugs. We successfully treated a patient with ADPKD for 14 months with lixivaptan who no longer could take tolvaptan because of liver side effects. During that time there were no changes in liver chemistry tests. We are now studying lixivaptan in a larger study (PA-ADPKD-303: The ALERT Study; NCT04152837) of similar ADPKD patients who had to discontinue tolvaptan because of liver side effects.

We performed a one-year dietary feasibility study in 28 adults with ADPKD who were overweight or obese. Participants completed a behavioral weight loss intervention based on either daily caloric restriction (DCR, reducing calorie intake per day) or intermittent fasting (severely reducing calorie intake three days per week). Both had clinically significant weight loss, but it was greater in the DCR group at one-year. The DCR group also had better dietary tolerability and adherence. As compared to historic data, kidney growth as measured by magnetic resonance imaging (MRI) was slower than expected in both groups. Kidney growth was strongly related to change in weight and change in abdominal fat measured by MRI (i.e., those who lost the most weight and abdominal fat had the slowest growth of their kidneys). These results will be used to design a longer and larger trial looking specifically at kidney growth with DCR.

Recently, our lab reported that dietary interventions to induce ketosis ameliorate disease progression in PKD animal models, and that this effect involves the natural ketone beta-hydroxybutyrate (BHB). Additionally, we have recently shown that renal microcrystals exacerbate disease progression in PKD models. Crystal burden can be minimized by administering citrate. We now show that a combination of citrate and BHB effectively inhibits PKD progression. These two compounds act on separate mechanisms to control disease progression and the combination of the two display synergistic effects on preventing cyst formation and cyst growth in young rats. In adult rats, the combination treatment leads to a partial reversal of existing renal cystic disease. This synergistic effect enables treatment with lower doses of citrate and BHB while maintaining the full beneficial effect. Both, citrate and BHB, are dietary supplements with minimal side effects. Our results suggest a highly feasible strategy for supporting kidney health in PKD.

We have developed a new 3D tubuloid model system for studying morphological, protein, and gene expressions changes that occur after acute loss of polycystins in an effort to better understand the initiating steps of cystogenesis. We found inactivation of the Pkd2 gene and loss of the PC2 protein causes the tubuloids to changes shape to a more cystic morphology and these morphological changes correlate with a distinct set of genes differentially regulated, with many of these genes associated with functions in the cell junctions and matrix interactions.