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Columns : Mar 15, 2007 ( )
AVI Is Taking Antisense Drugs to the Clinic
Company Develops New Approaches to Advancing its Technology Base!--h2>
Penguins have become celebrities, with real and animated versions starring in recent movies. But when several penguins at the Milwaukee zoo became ill with West Nile virus a few years ago, the antisense experts at AVI BioPharma (www.avibio.com) were the unsung heroes. Four hours after talking with a zoo veterinarian, they designed an antisense drug against West Nile virus.
Three penguins were treated, and all recovered a few days later. Before receiving the treatment, the penguins were gravely ill. “All the previous penguins that got ill had died,” says Patrick Iversen, Ph.D., senior vp of research and development at AVI.
The company’s rapid-response capability attracted the attention of the U.S. military. In December 2006, AVI received a two-year, $28-million research contract from the Defense Threat Reduction Agency to create treatments for biological warfare agents like the ebola, marburg, and junin viruses. The government promised additional funds to find treatments for dengue virus and to develop countermeasures for anthrax and ricin toxins.
One compound developed at AVI protected 100% of mice and 75% of monkeys from death following lethal doses of ebola virus. No ebola-infected monkeys had ever survived longer than eight days at the U.S. Army Medical Research Institute of Infectious Diseases laboratory. “We broke new ground because our compounds stopped an aggressive virus,” says Dr. Iversen.
AVI synthesizes antisense drugs with a patented third-generation NeuGene® technology that creates entirely synthetic phosphorodiamidate morpholino oligomers. These compounds complement a critical part of a human gene or a pathogen’s genetic information that makes it infectious.
Because the NeuGene backbone is totally synthetic, no human enzyme degrades the compounds. NeuGene drugs physically block the mRNA translation start site, rather than relying on RNase H. For typical antisense compounds, researchers must synthesize and test about 60 oligos, but “we only have to make one or two to find an active one,” says Dr. Iversen.
A search of GenBank for common sequences rapidly identifies the genetic information needed to construct NeuGene oligos. AVI scientists look for a good consensus of gene sequences to minimize the chance of an escape mutant in the environment. “Homology usually means conserved function, and that region should have the translation start site,” Dr. Iversen explains. AVI adds high-energy binding agents to maximize the binding of NeuGene oligos to target mRNAs.
The successful treatment of penguins led to AVI-4020, a treatment for West Nile virus in humans. Twelve patients have been treated, and the early reports indicate that the drug is effective against the neuroinvasive disease.
Farthest along in AVI’s pipeline is Resten-NG®, which targets c-myc, a key regulatory gene involved in cardiovascular restenosis. This narrowing of the coronary arteries plagues balloon angioplasty patients. Resten-NG reduced the restenosis rate by 75% in a recent Phase II trial, in which the drug was injected directly into the coronary artery through a catheter at the time of stent replacement. AVI is now exploring ways to deliver Resten-NG through special stents with Cook Group.
AVI is also working on AVI-4557, which targets cytochrome P450 enzymes involved in the metabolism of many common drugs. By changing the metabolism of a variety of marketed and experimental medications, AVI-4557 makes them last longer.
“We convert the phenotype of a rapid drug metabolizer to a slow drug metabolizer with AVI-4557,” says Dr. Iversen. When combined with AVI-4557, drugs that must be taken every few hours may be converted to once-daily or once-weekly dosing regimens.
Additional disease targets may open up with the recent discovery that NeuGene oligos cross the blood-brain barrier in healthy volunteers. “These molecules have molecular weights of 7,000 grams per mole,” says Dr. Iversen, “and the dogma is that only smaller molecules cross the blood-brain barrier.” This finding means that antisense drugs may have the potential to treat Alzheimer’s, schizophrenia, pain, or epilepsy.
In a stretch of the definition of antisense, AVI created ESPRIT (exon-skipping pre-RNA interference technology) to treat Duchenne Muscular Dystrophy (DMD). The gene dystrophin contains 79 exons, and a mutation in exon 51 causes one form of DMD. ESPRIT covers the defective exon with an antisense oligomer, generating a functional dystrophin protein that is missing the information in exon 51.
The slightly altered dystrophin mimics Becker’s muscular dystrophy, “a less severe version of muscular dystrophy with a higher quality of life than Duchenne’s,” says Dr. Iversen. In Becker’s muscular dystrophy, muscle weakness and other symptoms are milder and do not affect patients until middle-age, compared to striking in puberty in DMD. A proof-of-principle trial in young boys with DMD will take place in London this year.
Other NeuGene treatments are in the pipeline for hepatitis C, influenza A, polycystic kidney disease, and other genetic disorders. On the horizon are oral formulations of NeuGene therapies. “We’ve shown high oral bioavailablity in animals,” says Dr. Iversen, “but we still need to improve the formulations.”
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