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Revolutionizing ADPKD Treatment: Breakthrough Drug Unveils Unprecedented Benefits

By: Bhojranie Brahmanand, PharmD Candidate c/o 2025

The most prevalent manifestation within the spectrum of polycystic kidney diseases is recognized as autosomal dominant polycystic kidney disease (ADPKD). It is a genetic condition marked by the formation of fluid-filled cysts within the kidneys due to mutations in the PKD1 gene (located on chromosome 16) or the PKD2 gene (located on chromosome 4). In turn, these genetic alterations disrupt the typical function of proteins responsible for regulating cell growth and differentiation, specifically polycystin-1 and polycystin-2.1 Systemic manifestations include hypertension, valvular heart disease and intracebral aneurysms.2 With a global impact on over 12 million individuals, many of whom are the elderly, patients with this condition often find themselves in need of dialysis or a kidney transplant. The Food and Drug Administration (FDA)-approved drug for treating the disease, tolvaptan, impedes cyst growth. However, it has been associated with significant adverse effects such as frequent urination and potential liver damage.3 Now, researchers at the Massachusetts Institute of Technology (MIT) and Yale University School of Medicine have discovered that 11-beta compounds, originally developed as a potential cancer treatment, hold promise for treating ADPKD.4

Nearly 25 years ago, Robert Croy, MIT research scientist, developed these compounds which comprised of an aniline mustard. This deoxyribonucleic acid (DNA)-damaging agent had the capability to induce apoptosis in cancer cells. It was further revealed that these compounds can trigger oxidative stress by disrupting the mitochondria’s ability to generate adenosine triphosphate (ATP) which can later be used as a source of energy and nicotinamide adenine dinucleotide phosphate (NADPH) which is an antioxidant that neutralizes damaging free radicals.4

While normal cells can tolerate oxidative stress, cystic cells have a low tolerance for oxidative stress and succumb to the treatment ultimately leading to cell death. Tumor cells and kidney cyst cells were observed to exhibit elevated levels of free radicals due to the induced oxidative stress. When exposed to the 11-beta compounds, these cells endure heightened oxidative stress, resulting in further depletion of NADPH. This ultimately pushes them beyond their threshold for toleration. While normal cells typically survive this treatment, cystic cells will undergo cell death as they surpass the threshold.4

In an established early inactivation model for ADPKD, researchers used Pkd1fl/fl; Pkhd1-Cre mice. PKD1 was selectively inactivated in the collecting duct by postnatal day seven (P7). The mice received daily intraperitoneal injections of 11-beta-dichloro at 10 mg/kg starting from postnatal day 10 (P10) to P23. This treatment demonstrated significant structural improvement in PKD, as evidenced by gross morphology and reduced kidney weight: body weight ratio with cystic area percentage. The slowed cyst growth was associated with improved kidney function, indicated by lower levels of blood urea nitrogen and serum creatinine compared to the control group. The treatment was well-tolerated with no significant weight loss observed in the treated animals.6

Another model of ADPKD that closely mimics the gradual progression seen in humans is the “adult Pax8” model. In this model, mice were exposed to doxycycline in their drinking water from postnatal day 28 to day 42, deactivating PKD1 in a substantial portion of the nephron. Starting at postnatal day 42, the mice were treated for 12 weeks intraperitoneal injections of 11beta-dichloro three times a week at a dose of 10 mg/kg body weight. At 18 weeks of age, mice treated with 11beta-dichloro exhibited a less severe form of polycystic kidney disease compared to those treated with the vehicle. The treatment was well tolerated, with no significant body weight loss observed in the treated animals compared to the controls. This aligns with prior mouse toxicity studies on 11beta-dichloro, which confirmed that the employed dose of 10 mg/kg would not result in adverse effects.6

A modified form of the compound, 11-beta-dipropyl, which lacks any direct DNA-damaging potential, has been identified as a safer option for human use. The findings indicated its efficacy to be comparable to that of 11-beta-dicholoro. It is important to highlight that, in all the experiments conducted, the treatment did not seem to have any adverse effects on healthy kidney cells. In addition to recovering kidney function, the therapy demonstrated improvement in various clinical aspects of ADPKD. Biomarkers indicating tissue inflammation and fibrosis were reduced in the treated mice. These results reinforce the idea that 11-beta compounds targeting mitochondria and induce oxidative stress are the pivotal mechanisms through which these compounds induce selective apoptosis of cystic cells and enhance preclinical outcomes in mouse models of ADPKD.4

The findings have suggested that administering 11-beta compounds to patients at intervals of a few months, or annually could substantially slow down the progression of the disease. This approach may offer an alternative to continuous and demanding antiproliferative treatments like tolvaptan.6 Researchers hope to run further tests on 11-beta-dipropyl, as well as develop ways to produce it on a larger scale. They also plan to explore related compounds that could be good drug candidates for PKD. It is evident to say that 11-beta compounds hold strong potential as a compelling therapeutic option for ADPKD patients. This groundbreaking finding contributes to the forefront of impactful medical interventions.

References

  1. Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. J Cell Biol. 2010;191(4):701-710. doi:10.1083/jcb.201006173
  2. Bais T, Gansevoort RT, Meijer E. Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease. Drugs. 2022;82(10):1095-1115. doi:10.1007/s40265-022-01745-9
  3. Zhou L, Tian Y, Ma L, Li WG. Tolvaptan ameliorated kidney function for one elderly autosomal dominant polycystic kidney disease patient: A case report. World J Clin Cases. 2022;10(31):11500-11507. doi:10.12998/wjcc.v10.i31.11500
  4. Trafton A. A new drug candidate can shrink kidney cysts. MIT News. January 22, 2024. Accessed April 23, 2024. https://news.mit.edu/2024/new-drug-candidate-can-shrink-kidney-cysts-0122. 
  5. Gyurászová M, Gurecká R, Bábíčková J, Tóthová Ľ. Oxidative Stress in the Pathophysiology of Kidney Disease: Implications for Noninvasive Monitoring and Identification of Biomarkers. Oxid Med Cell Longev. 2020;2020:5478708. Published 2020 Jan 23. doi:10.1155/2020/5478708
  6. Fedeles BI, Bhardwaj R, Ishikawa Y, et al. A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress. Proc Natl Acad Sci U S A. 2024;121(4):e2317344121. doi:10.1073/pnas.2317344121
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