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Trial Underway Testing RNA Therapy for Rare Liver Disorder

Liver biopsy from AATD patient

Liver biopsy from patient with alpha-1 antitrypsin deficiency (Jerard Gardner, WikiMedia Commons)

5 May 2015. An early-stage clinical trial is testing a therapy derived from genetic material to treat alpha-1 antitrypsin deficiency, a rare inherited disease affecting the liver and lungs. The therapy, code-named ARC-AAT, is developed by Arrowhead Research Corporation, a biopharmaceutical company in Pasadena, California.

Alpha-1 antitrypsin deficiency, or AATD, is caused by a mutation in the gene that makes the protein alpha-1 antitrypsin, produced in the liver and protecting the body from an enzyme called neutrophil elastase. Without the protection of alpha-1 antitrypsin, neutrophil elastase destroys air sacs in the lungs, with a condition similar to chronic obstructive pulmonary disease or COPD. About 1 in 10 infants and 15 percent of adults with AATD also develop liver disease leading to cirrhosis or scar tissue in the liver.

AATD affects about 1 in 2,500 individuals, mainly of European descent. While alpha-1 antitrypsin augmentation therapies can treat the lung conditions, the only recourse today for AATD patients with liver disease is a liver transplant.

Arrowhead’s technology is based on ribonucleic acid or RNA interference (RNAi), a natural process to silence the expression of genes causing disease. RNA is genetic material related to DNA that the body uses to transmit genetic information to cells and synthesize proteins. RNA interference targets specific genes, making it a potentially powerful therapeutic technique, while minimizing damage to other genes, thus limiting side effects.

The company delivers RNAi molecules in nanoscale — 5 to 20 nanometer — packets called dynamic polyconjugates made of biocompatible polymers, combined with signaling molecules that seek out specific cell targets in the body. The dynamic polyconjugate packet binds to the cells, releasing the RNAi molecules to turn on or off the targeted genes.

The targeted gene for ARC-AAT in this case is the mutated gene that fails to produce alpha-1 antitrypsin, known as the Z variation. Once delivered, ARC-AAT aims to reduce expression of the Z variation gene, thus reducing production of the damaging protein and slowing or stopping the progression of liver disease in AATD patients.

The clinical trial is a two-part study of ARC-AAT’s safety and actions in the body, first with healthy volunteers and then with AATD patients. A total of 48 individuals are enrolled at a test site in Australia, randomly assigned 2-to-1 to receive ARC-AAT or the placebo. In each part of the trial, the study is testing vital signs and indicators of adverse reactions as measures of the therapy’s safety, as well as various biochemical indicators as measures of activity in the body.

Arrowhead says the first part of the study, testing 3 dosage levels of ARC-AAT injections against a placebo with healthy volunteers, is now complete, with results showing the treatments at all dosage levels were well-tolerated. The company says dosing of AATD patients is now underway, with results expected by the end of 2015.

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