The paradigmatic gene therapy technique involves slipping new genes into cells on the backs of modified viruses, although other methods exist. Wilmington, Del.-based Orphagenix is championing one of these lesser-known approaches against some lesser-known diseases.
"Many of them are life-threatening and there are no other cures," says Orphagenix president and CEO, Michael Herr. That, and their rarity, will let the company benefit from federal incentives designed to encourage drug development for such conditions, he adds. A key incentive is the Orphan Drug Act of 1983.
Orphagenix is using a family of patented techniques designed to correct point mutations, developed by researchers led by molecular biologist Eric Kmiec of the University of Delaware in Newark. The basic approach, called targeted gene alteration, is to introduce into cells oligonucleotides that are complementary to a gene with an incorrect base, except at the point corresponding to that base. If the oligonucleotide binds to the gene, natural enzymes can make the desired change by repairing the resulting mismatch, as they do normally in fixing DNA copying errors.
Researchers have reported some successes with this in animals, using various drug delivery methods, though human studies haven't been done. "We feel pretty confident that it's just a matter of technical effort to follow this through" into clinical success, Herr says.
Others have shown less enthusiasm. One factor is that virus-based gene therapies have historically surpassed the nonviral therapies in popularity, says Ted Friedmann, director of the Program in Human Gene Therapy at the University of California, San Diego. That's probably because viruses are obvious candidates to overcome gene therapy's biggest hurdle, he says: how to sneak genetic information into the genome itself, where it's needed.
Viruses do such work "for a living," Friedmann notes; they're also "at the heart of what has been called unequivocal clinical success" in gene therapy trials. However, a few trial subjects have died, raising grave concerns. No gene therapies have Food and Drug Administration approval. Alternative techniques are needed, Friedmann says, because different diseases will require different strategies. The nonviral approach could "fix a spelling error in a gene, and leave no other footprint that you've been there," he says - a Holy Grail for much gene therapy.
Kmiec, Orphagenix's scientific cofounder, has faced bigger difficulties than just a relative disinterest in nonviral techniques; his team's work has met with criticism. In 1997 and 2001, different researchers sent letters to Science expressing disbelief over certain findings that seemed wildly successful, yet problematic to replicate.
Kmiec has conceded that widely varying success rates, often unexplained, have bedeviled his approach, whose success in a given model is typically gauged by the fraction of cells receiving successful DNA correction. Only a fraction of cells must be fixed to alleviate certain diseases. Kmiec insists that time has reaffirmed his ideas. Since the criticisms, many independent laboratories' findings have validated his technology to some degree. Lately, Herr says, investigators successfully applied Kmiec's approach to a mouse model of retinal degeneration, which was reported in the May 2, 2007, issue of Molecular Vision.
Referring to Kmiec as a "pioneer," Herr says Orphagenix is applying Kmiec's techniques to four point-mutation diseases: sickle-cell anemia, spinal muscular atrophy (floppy baby syndrome), juvenile macular degeneration (an eye disease), and alpha-1 antitrypsin deficiency (can cause lung and liver failure). Altogether, these affect an estimated 225,000 people nationwide. "We're looking for commercial collaborators to help transfer these therapies into the clinic" after clinical proof of concept is established for each, Herr says. "All our avenues are open."