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.”