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Data Point to Regulus Alport Drug Use in Late-stage Disease, Other Kidney Diseases


NEW YORK (GenomeWeb) ― Researchers from Sanofi recently reported preclinical data showing that Regulus Therapeutics' microRNA-21 inhibitor RG-012 can have a therapeutic benefit even in the late stages of Alport syndrome and that it can enhance the effect of the kidney protectant ramipril.

Separately, late last week, Regulus, Sanofi, and collaborators at the University of Washington published data demonstrating that inhibition of the miRNA can improve the survival and prevent disease progression in a mouse model of Alport syndrome by stimulating metabolic pathways and suggesting its utility in other kidney diseases.

RG-012 is slated to enter Phase I testing in healthy volunteers in the first half of 2015, with a Phase II proof-of-concept study beginning later in the year. Pursuant to the terms of their recently renegotiated partnership, Sanofi has the right to option RG-012 after Regulus has demonstrated human proof of concept with the drug.

Alport syndrome is caused by mutations in three genes that affect production of the type IV collagen family of proteins. The result is a disruption to the structure of the glomerular basement membrane, increased expression of miRNA-21, an increase in fibrosis, and the loss of renal function, which ultimately leads to end-stage renal disease.

Earlier this year, Regulus announced that it had made RG-012, a miR-21 inhibitor delivered subcutaneously using GalNAc conjugates, its second pipeline candidate behind the hepatitis C treatment RG-101. Sanofi scientists presented data at the American Society of Nephrology's Kidney Week 2014 meeting this month demonstrating that the drug candidate could improve kidney function in an Alport mouse model even when treatment was delayed.

According to the data, when RG-012 was administered to animals nine weeks old and in the late stages of chronic kidney disease, blood urea nitrogen (BUN) measurements significantly improved by week 15. Additionally, the average lifespan of the mice was extended even when treatment started at 13 weeks.

Sanofi further reported that RG-012 could enhance the effect of ramipril, an ACE inhibitor used to treat high blood pressure, congestive heart failure, and kidney damage associated with diabetes.

Specifically, BUN levels of Alport mice treated with RG-012 were significantly lower than those receiving ramipril, and the combination of the drugs had additive effects on kidney function while improving survival.

These data, Sanofi said, suggest that RG-012 may be effective for both early and late-stage Alport syndrome.

Meanwhile, in a paper appearing in The Journal of Clinical Investigation, Regulus investigators reported that miR-21 inhibition resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, in a mouse model of Alport neuropathy. This effect, the researchers noted in their study, was observed in over 100 mice treated in seven independent experiments.

The Regulus team also evaluated the effect of miR-21 silencing on survival and found that knocking down the miRNA could increase the median survival of the mice from 76 days to 108 days, and that this effect was dose dependent.

Treated animals also experienced reductions in glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Notably, miR-21 antagonism also enhanced mitochondrial function, which lowered the production of mitochondrial reactive oxygen species to preserve tubular functioning, according to the JCI study.

Inhibition of miR-21 was also protective against induced fibrogenesis and inflammation in glomerular and interstitial cells, an effect the scientists attributed to the derepression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) — a target of miR-21 that is involved in fatty acid oxidation, detoxification, mitochondrial biogenesis, and anti-inflammatory signaling.

Overall, miR-21 silencing can slow the downstream consequences of mutations in type IV collagen genes that ultimately drive progression of Alport nephropathy, the team wrote in their paper.

As such, the therapeutic approach may also hold promise for stopping the progression of other forms of chronic kidney disease, they noted.

There are many miR-21 targets in the kidney, including multiple regulators of metabolism in mitochondria and the cytosol, and many of these gene targets are derepressed by the miRNA's inhibition, they added. The miRNA also appears to provoke stress responses in the epithelium and glomerular cells, suggesting a "broad role as an amplifier of chronic disease."