Genetic Liver-Targeted Diseases
Primary Hyperoxaluria Type 1 (PH1)
Primary hyperoxaluria type 1 (PH1) is a severe, rare, genetic disorder of metabolism in the liver that leads to severe damage to the kidneys, often culminating in kidney failure. The disease is a recessive condition, meaning that it appears only in individuals who have received two copies (one from each parent) of a disease-causing variant of a gene.
PH1 can be fatal unless the patient undergoes a dual liver and kidney transplant, a major surgical procedure that is often difficult to perform due to the lack of donors and the threat of organ rejection. Even in the event of a successful transplant, the patient must endure the risks and complications of major surgery and face a lifetime of therapy with immunosuppressant drugs, which have substantial associated risks.
What Causes PH1?
PH1 is characterized by a genetic deficiency of the liver enzyme alanine:glyoxylate-aminotransferase (AGT), which is encoded by the AGXT gene. AGT is a critical enzyme that causes the metabolic breakdown of a naturally occurring component of collagen called hydroxyproline. AGT deficiency causes a buildup of glyoxylate, which is readily converted into oxalate, the metabolite that characterizes PH1.
Oxalate is highly insoluble and crystalizes at certain concentrations in the presence of calcium ions. In individuals with PH1, crystals of calcium oxalate form in the renal (kidney) tubules, a condition known as nephrocalcinosis, which often leads to chronic and painful cases of kidney stones (nephrolithiasis) and subsequent fibrosis (scarring). Despite the typical intervention of massive intake of water (i.e., 3-4 liters/day) in an attempt to dilute the oxalate, many patients progress to renal failure or end-stage renal disease (ESRD) and require a kidney transplant. Despite undergoing frequent dialysis, PH1 patients with ESRD may still experience a buildup of oxalate in the bone, skin, heart and retina, with concomitant debilitating complications.
Currently, the most definitive therapy for PH1 involves a dual liver and kidney transplant. However, there are no potentially curative therapies available for patients with PH1. While the true prevalence of PH1 is unknown, it is estimated to be one to three cases per one million people and may afflict as many as six or seven people per million. Fifty percent of patients with PH1 reach ESRD by their mid-30s.
Why Focus on PH1?
We believe that there is a strong rationale for focusing our RNAi technology on the development of product candidates for the treatment of PH1. The hydroxyproline breakdown metabolic pathway that is disrupted in PH1 consists of a number of enzymes. The gene encoding the final enzyme in the pathway, alanine-glyoxylate aminotransferase 1 (AGT1), is mutated in patients with PH1. Under normal circumstances, AGT1 metabolizes oxalate precursors into the harmless amino acid glycine, which is then used by the body or excreted. But when AGT1 function is disrupted due to mutation, oxalate begins to build up, resulting in progressive loss of kidney function and, ultimately, kidney failure. DCR-PHXC is designed to block the production of oxalate in patients with PH1.
Using DCR-PHXC, and also other GalXC molecules synthesized during the discovery and optimization of DCR-PHXC, we have shown that RNAi can be used to block the production of oxalate in an animal model of PH1. These studies employ mice in which the gene encoding AGT1 has been genetically deleted to create an animal model of PH1. Similar to human patients, these mice have elevated levels of oxalate in their urine. A single dose of DCR-PHXC of 5 mg/kg delivered subcutaneously in the animal model of PH1 silences target gene expression by greater than 90% and results normalization or near normalization of urinary and plasma oxalate levels. We believe these results, if achievable in patients with PH1, would be highly beneficial.