The preclinical studies showed that DCR-PH1 provides potent and long-term inhibition of HAO1, a gene implicated in the pathogenesis of PH1. In a genetically modified mouse model of PH1, researchers reported a 97 percent reduction of the HAO1 transcript in the liver after a single dose of DCR-PH1 and a significant reduction in urinary oxalate levels, a key marker of the disease. In mice treated with DCR-PH1, urinary oxalate levels returned to near baseline levels, similar to normal mice.
"Physicians, patients and families managing PH1 currently have limited to no effective treatment for this severe and progressive disease," noted
PH1 occurs when a liver enzyme called AGT does not function properly due to a genetic defect, inducing the liver to over-produce a metabolite called oxalate. While oxalate has no clinical effect in a healthy population, it is concentrated in the urine by the kidneys of patients with PH1, forming calcium oxalate crystals that can lead to chronic and painful cases of kidney stones, scarring of the kidney and end-stage renal disease.
DCR-PH1 is engineered to address the pathology of PH1 by targeting and destroying the messenger RNA (mRNA) produced by HAO1, a gene that encodes glycolate oxidase, a protein involved in producing oxalate. By reducing oxalate production, this approach is designed to prevent the complications of PH1.
"Our preclinical studies indicate that inhibition of the gene HAO1 prevents expression of glycolate oxidase, as expected, and may therefore reduce significantly the abnormally high oxalate production found in patients with PH1," commented Dr. Salido. "By blocking production of glycolate oxidase in the liver, DCR-PH1 may prevent the severe kidney damage that is characteristic of PH1."
"Dr. Salido's data lend further support to the use of the Dicer Substrate RNAi technology platform, which we believe improves upon existing RNAi technologies in the treatment of rare, genetically defined diseases involving the liver," stated
PH1 is characterized by a genetic deficiency of the liver enzyme AGT (alanine:glyoxalate aminotransferase), which is encoded by the AGXT gene. AGT deficiency induces overproduction of oxalate by the liver, resulting in the formation of crystals of calcium oxalate in the kidneys. Oxalate crystal formation often leads to chronic and painful cases of kidney stones and subsequent fibrosis (scarring), which is known as nephrocalcinosis. Many patients progress to end-stage renal disease (ESRD) and require dialysis or transplant. Aside from having to endure frequent dialysis, PH1 patients with ESRD may experience a build-up of oxalate in the bone, skin, heart and retina, with concomitant debilitating complications. Currently, aside from dual liver and kidney transplant, there are no highly effective therapeutic options for most patients with PH1. While the true prevalence of primary hyperoxaluria is unknown, the estimated prevalence of PH1 is 1 to 3 cases per 1 million people.1 Fifty percent of patients with PH1 reach ESRD by their late 30s.2 About EnCoreTM Technology Dicerna uses EnCore lipid nanoparticles, the company's proprietary delivery system, to deliver the Dicer Substrate RNA (DsiRNA) molecule DCR-PH1 to liver tissues. Once in the liver, the DsiRNA leads to the specific destruction of the gene transcript that encodes the enzyme glycolate oxidase, which is responsible for the pathologic accumulation of oxalate in PH1. This process is highly specific for the targeted gene. About RNAi RNAi is a highly potent and specific mechanism for regulating the activity of a targeted gene. In this biological process, certain double-stranded RNA molecules known as short interfering RNAs (siRNAs) bind to complementary messenger RNAs (mRNAs) and recruit proteins that break the chemical bonds that hold mRNAs together, preventing the mRNAs from transmitting their protein-building instructions.
Dicerna's proprietary RNAi molecules are known as Dicer Substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna's discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi. About
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