By David N. Leff
Editor's note: Science Scan is a round-up of recently published biotechnology-related research.
Gene therapists are still searching for the ideal DNA delivery system. Viral vectors have their shortcomings; DNA shot from guns or injected naked leave much to be desired; liposome microcarriers have yet to prove superiority.
Into this arena comes a report in the latest Proceedings of the National Academy of Sciences (PNAS) dated Dec. 23, 1997. Its title: "In vivo gene delivery to the liver using reconstituted chylomicron remnants as a novel nonviral vector."
Chylomicrons are the body's own microcarriers. These lipid droplets, 0.8 to 5 nanometers in diameter, are the largest lipoproteins; they transport fatty acids and glycerol ingested in the diet to fat cells and muscles, for energy utilization and storage. Their empty remnants then proceed to the liver for reprocessing.
At the University of Pittsburgh, the PNAS paper's senior author, molecular pharmacologist Leaf Huang, coated genes encoding human alpha-1-antitrypsin with lipids and oil in stable reconstituted chylomicron structures about 100 nanometers across. They succeeded in getting 65 percent of the DNA incorporated into the oil core.
After the Pittsburgh team injected this plasmid into the livers of mice, via the portal vein, they found a 100-fold greater expression of the gene compared with control rodents, which got injections of naked DNA. Though highest in their livers, this gene activity also reached the lungs and kidneys of the treated mice.
"By selecting genes specific to a patient's disorder," Huang said, "eventually we may be able to use this delivery system to jump-start the body's production of therapeutic proteins and enzymes. This will offer patients with hepatoma, viral hepatitis, cancer and other liver disorders a viable hepatic gene therapy."
Roche-Cincinnati Team Shows Leptin Needs
Side-Kick Receptor To Slim Down Weight — In Rats
Leptin, as just about everyone knows by now, is a hormone that suppresses appetite, and thus whittles down obesity by acting on the central nervous system.
What few know is that leptin doesn't act alone. It needs a receptor for another brain hormone, melanocortin, to get its eat-less, slim-down message across.
Rats that had their melanocortin receptors (MR) chemically blocked, lost their leptin's effect, ate their greedy fill, and waxed fat. But rodents whose melanocortin receptors remained intact, ingested less food and lost weight. Their leptin was on the job.
The researchers who proved this point in vivo reported their finding in Nature, Nov. 27, 1997. Their brief communiqué bore the title: "Melanocortin receptors in leptin effects." Its co-authors included molecular psychiatrist Randy Seeley, at the University of Cincinnati, Ohio, and Keith Yagaloff, research leader in metabolic diseases at Hoffmann-La Roche Inc., Nutley, N. J.
They pointed out that agonists (mimics) of the MRs reduced food intake, whereas targeted mutation of the receptor caused obesity.
Leptin's own receptors, they noted, are on neurons in the brain area that synthesizes melanocortins, making it "seem likely that leptin-induced reductions in food intake might be mediated by the melanocortin system."
"A better understanding of this receptor," Yagaloff observed, "may enable us to develop new therapeutic treatments for obesity," especially in leptin-resistant individuals.
Free-Living Granule In Cells Of Toxoplasma Parasite Succumbs To Antibiotics, Clue To Antimalarial Drugs
Besides being a sometimes lethal pathogen itself, especially in AIDS patients and newborns, Toxoplasma gondii, (as in toxoplasmosis), belongs to a family of parasites that includes Plasmodium (as in malaria), among others. These scourges comprise a phylum of protozoa called the apicomplexans. (See BioWorld Today, Jan. 10, 1996, p. 1.)
Their claim to fame is possession of an intracellular organelle, the apicoplast, which seems to be the evolutionary relic of a one-cell green alga that took up symbiotic housekeeping in the apicomplexans long ago. To this day, apicoplasts — a bit like mitochondria — maintain their own separate 35-kilobase circular DNA genome.
Molecular parasitologists at the University of Pennsylvania, in Philadelphia, now report that this maverick genome succumbs to a broad-spectrum antibiotic, ciprofloraxin. What's more, despite the organelle's fiercely independent lifestyle, when it gets clobbered, so does the whole parasite.
As malaria develops drug resistance to more and more antimalarial compounds, this finding strikes its discoverers as worth pursuing. Their report, titled "A plastid organelle as a drug target in apicomplexan parasites," appeared in Nature, Nov. 27, 1997.
"Our results," the authors wrote, "directly link apicoplast function with parasite survival, validating this intriguing organelle as an effective target for parasiticidal drug design." *