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RNA Drug Delivery Technique Shown Safe in Monkeys

RNA molecule illustration

RNA molecule illustration (Nicolle Rager Fuller, National Science Foundation)

8 November 2016. A biotechnology company reports a drug delivery method combining nanoscale lipid particles and biocompatible polymers enables the safe production of synthetic RNA-based proteins in monkeys. PhaseRx Inc. in Seattle reported the results today on its web site.

PhaseRX is a developer of treatments for enzyme deficiencies, particularly urea cycle disorders, rare genetic diseases affecting children, where the lack of needed enzymes allows for ammonia to build up in the blood. The elevated ammonia levels eventually reach the brain, causing irreversible brain damage, coma, or death. National Urea Cycle Disorders Foundation says incidence of these conditions is about 1 in 8,500 births, with liver transplants as the only known remedy.

The company’s technology aims to replaced the missing or damaged enzymes allowing the body to function normally. Its intracellular enzyme replacement therapy, or i-ERT, delivers messenger RNA, a nucleic acid related to DNA used by cells to produce the amino acids in proteins for carrying out functions in the body, in this case inside liver cells known as hepatocytes.

Most enzyme replacement therapies use direct infusions of enzymes, but in hepatocytes the enzymes are missing inside the cell. Thus PhaseRX’s i-ERT technology is designed to synthesize the enzyme inside the hepatocyte, using the messenger RNA delivered in the treatments. The company’s lead product, code-named PRX-OTC, is designed to use i-ERT to treat ornithine transcarbamylase deficiency, a type of urea cycle disorder.

The delivery method designed by PhaseRX is called hybrid mRNA, for messenger RNA, technology, The “hybrid” in this case refers to the use of two materials to package the messenger RNA and deliver it inside the cell. The therapeutic messenger RNA is encased in nanoscale lipid, or natural oil, nanoparticles, which keeps it stable as it travels through the blood stream. When the messenger RNA is taken up in the liver, a synthetic polymer enables the messenger RNA to penetrate the hepatocyte cell membrane, where it can produce the healthy enzyme.

PhaseRX earlier tested the i-ERT and hybrid mRNA technologies in lab mice, but needed validation with higher-order species more resembling humans. In tests with monkeys, the company delivered messenger RNA coding the human erythropoietin protein produced in a number of cells in the body including hepatocytes. The tests aimed to deliver 3 levels of erythropoietin protein, some doses well in excess of normal physiological needs.

The results show the hybrid mRNA delivered the erythropoietin protein to the liver, as shown by subsequent increases in reticulocytes, immature red blood cells indicating normal erythropoietin functioning, that matched the levels of messenger RNA in the 3 doses. The company also reports the test monkeys tolerated the treatments, with no changes in other liver enzymes, or higher production of proteins indicating an abnormal immune response.

PhaseRX says it expects to complete preclinical tests of PRX-OTC in 2017, and with authorization from FDA, begin clinical trials in 2018.

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