From Nature.com, by Andrea Aguilar
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inheritable human diseases and leads to renal failure; however, no effective treatment exists. In a new study, Xueying Lin and colleagues used TALEN-mediated gene editing to establish a zebrafish model of ADPKD and showed that activating autophagy reduces cystogenesis and restores renal function.
“As PKD1 is the most common causative gene for PKD, we generated zebrafish pkd1a mutants,” explains Lin. These pkd1a-null fish had pronephric cysts, mTOR hyperactivation and reduced autophagic flux — a feature also present in kidney epithelial cells from PKD1-null mice and patients with ADPKD.
To pinpoint the contribution of defective autophagy to cystogenesis, the researchers reduced the levels of ATG5 — a core autophagy protein — in pkd1a-deficient fish. This inhibition of autophagy increased the incidence of cyst formation caused by pkd1a depletion at an early time point (48% versus 10%). Conversely, activation of autophagy with a short peptide of beclin-1, with carbamazepine or minoxidil, or through mTOR inhibition with rapamycin reduced cyst formation and restored renal function in pkd1a-deficient fish. “Although abnormal autophagy had previously been shown in PKD models, our study demonstrates that autophagy activation exerts therapeutic benefits in PKD,” says Lin.
Inhibition of the mTOR pathway using rapamycin is a candidate therapy for PKD but high doses of this agent are toxic and have systemic adverse effects. Here, the researchers showed that the combination of a 10-fold reduced dose of rapamycin with carbamazepine had a synergistic effect and suppressed cystogenesis as efficiently as a high dose of rapamycin.
Going forward, the researchers plan to take advantage of the zebrafish embryo, an efficient in vivo model for small molecule screening. “We plan to screen known autophagy modulators, especially those already in clinical use, to identify effective new drugs for PKD.”
From Patent Application
RESUMEN
The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and/or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and/or killing a cyst cell.
The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and/or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and/or killing a cyst cell.
DESCRIPCIÓN (El texto procesado por OCR puede contener errores)
METHODS FOR TREATING POLYCYSTIC KIDNEY DISEASE AND
POLYCYSTIC LIVER DISEASE
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S. S.N. 61/891,377, filed October 15, 2013, which is incorporated herein by reference.
GOVERNMENT SUPPORT
[0002] This invention was made with U.S. Government support under grant numbers DK079310, CA077743, and DK007276 awarded by the National Institutes of Health and under Contract number W81XWH-06-1-0183 awarded by the Army Medical Research and Material Command. The U.S. Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts in the kidneys of a subject. PKD is among the most common life-threatening genetic diseases in the world and is a leading cause of end-stage renal failure and a common indication for dialysis or renal transplantation (Wilson, N. Engl. J. Med. 2004, 350, 151-164). The kidneys filter wastes and extra fluid from the blood to form urine and also regulate amounts of certain vital substances in the subject. When cysts form in the kidneys, they are filled with fluid. PKD cysts can profoundly enlarge the kidneys while replacing much of the normal structure, resulting in reduced kidney function and leading to kidney failure. PKS includes autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD is the more common inherited form of PKD, whereas ARPKD is a rare inherited form. It has been reported that mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PCI) and polycystin-2 (PC2), respectively, may be responsible for ADPKD (Gallagher et ah, Adv. Chronic Kidney Dis. 2010, 17(2): 118-130; The European Polycystic Kidney Disease Consortium, Cell 1994, 78:725; The International Polycystic Kidney Disease Consortium, Cell 1995, 81:289-298; Mochizuki et al, Science 1996, 272: 1339-1342; The European Polycystic Kidney Disease Consortium, Cell 1994, 77, 881-894). A causative gene ARPKD has been thought to be PKHD1, which encodes fibrocystin/polyductin (FPC).
[0004] PKD can also cause cysts in the liver and problems in other organs, such as blood vessels in the brain and heart. For example, polycystic liver disease (PLD) is an inherited condition characterized by the presence of multiple scattered cysts of biliary origin throughout the liver parenchyma (Fedeles et ah, Nature Genetics 2011, 43(7):639-648; Qian et ah, Hepatology 2003, 37, 164-171). PLD occurs frequently as an extra-renal manifestation of ADPKD, but it also exists as a distinct dominantly inherited genetic entity without kidney cysts (autosomal dominant PLD (ADPLD)). Mutations in PRKCSH or SEC63 may underlie isolated ADPLD (Reynolds et al., Am. J. Hum. Genet. 2000, 67, 1598-1604; Li et al., Am. J. Hum. Genet. 2003, 72, 691-703; Davila et al., Nat. Genet. 2004, 36, 575-577; Drenth et al, Nat. Genet. 2003, 33, 345-347).
[0005] PCI, PC2, and FPC, along with one Meckel syndrome gene product (MKS3) (Smith et ah, Nat. Genet. 2006, 38, 191-196), have been reported to be the only integral membrane proteins mutated in cilia-associated fibrocystic diseases (Sharma et ah, Curr. Top. Dev. Biol. 2008, 85, 371-427). ADPKD and ADPLD are also unique in that they may be the only dominantly inherited traits among the cilia-associated diseases (Menezes et ah, Methods Cell Biol. 2009, 94, 273-297).
[0006] Subjects with PKD {e.g., ADPKD) may be treated by hemodialysis, peritoneal dialysis, or renal transplantation. Treatment of PLD {e.g., ADPLD) may include cyst aspiration, cyst fenestration, liver resection, and liver transplantation. Currently, there are no FDA-approved therapeutic drugs that directly target PKD. Several clinical trials are underway testing the cAMP inhibitor (Tolvaptan) or excessive intake of water as means to slow down the progression of PKD. Certain mTOR inhibitors, such as rapamycin, have been studied in clinical trials, but those mTOR inhibitors have not shown significant clinical effectiveness. Therefore, there remains a need for improved treatment of PKD and PLD.
SUMMARY OF THE INVENTION
[0007] The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and/or perturb mitochondrial function of a cyst cell {e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating and/or preventing PKD or PLD, inhibiting the growth of a cyst cell, and/or killing a cyst cell. [Read more]
Gift of Life
A Virginia man is giving his wife something really big for their 20th wedding anniversary instead of traditional china: his kidney.
For six years, Scott Chafian had wanted to donate his kidney to his wife, Cindy, who suffers from polycystic kidney disease and has been on dialysis for almost two years.
She wouldn't take it until her condition deteriorated.
"I hit kind of rock bottom, and I looked at him and I said OK, I'm ready," Cindy Chafian told WTKR-TV.
The transplant surgery is scheduled for Jan. 24 -- the day before their 20th anniversary.
The Chafians learned the date five days before Christmas.
"He called me and he told me that everything was a go. He gave me a date and that was the first time I allowed myself any emotion and I actually cried," she said.
The family is accepting wedding gifts in the form of donations at GoFundMe.They need money for the surgery and while they are not working while recovering. Through Monday, a total of $1,835 of their $5,000 goal was raised.
The posting on the website says: "This is a beautiful milestone in marriage. Usually couples get to throw a big party or maybe renew their vows. But they won't be getting to do any of that. In fact they'll both be in separate hospital rooms recovering."
A doctor said Scott Chafian is the "cleanest donor" he has seen in five years, according to the website.
"To know that he's kind of giving me that ability is even more of an amazing gift," she told the TV station. He powers me in so many ways ... he is literally going to give me life. So it's an amazing gift."
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