By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

The cutoff of blood flow to the brain is the cause of ischemic stroke. Right?

Half right.

A contributing cause is the immune system¿s overzealous response to the inflammatory brain damage it perceives as an insult to be remedied. White blood cells rush to the scene of the crime, but their fix-it efforts often aggravate the stroke patient¿s injury.

But the body also secretes a countervailing molecule called activated protein C (APC), which exerts anticoagulant and anti-inflammatory effects. Its performance in a mouse model of stroke is reported in the April 3, 2001, issue of the journal Circulation. The paper is titled: ¿Anti-inflammatory, antithrombotic and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke.¿

¿The damage from a stroke doesn¿t happen just because the brain is deprived of oxygen and other nutrients,¿ observed the article¿s senior author, neurosurgeon Berislav Zlokovic, at the University of Rochester Medical Center in New York. ¿The influx of white blood cells into the brain,¿ he pointed out, ¿causes tremendous damage. The role of inflammation in inflicting damage to the brain is only recently becoming appreciated.¿

The co-authors induced a stroke attack in mice by plugging their middle cerebral arteries (under anesthesia), thus interrupting blood flow for one hour, then reperfused the blood vessel. Fifteen minutes before or 10 minutes after the occlusion, they administered APC via intravenous injection. Animals that received APC were much more likely to survive their strokes than control counterparts, which did not get the drug. Eight of 12 control animals died within 24 hours.

The APC animals acquired a number of benefits: their brains had more blood flow and less swelling; their blood was less likely to clot; a smaller region of the brain was affected by the stroke; and their brains contained 90 percent fewer neutrophils than did control mice.

Eli Lilly & Co., of Indianapolis, is developing a genetically engineered version of APC, for use against sepsis, an often-fatal blood disorder. A study in the March 8, 2001, issue of the New England Journal of Medicine showed that APC reduced by 20 percent the rate of death in sepsis patients.

Comment In Science Sounds Alarm That Near Future Could Bring Germ-Line Child Enhancement

The prospect of cloning human beings continues to be a hot ¿ and hotly renounced and denounced ¿ topic of public discourse. Now gene therapy aimed at tampering with an unborn child¿s germ-line endowment has entered the lists.

The journal Human Reproduction reported in March that intentionally modified mitochondrial DNA had been transmitted to human offspring, effectively altering their germ line.

This development gave rise to a one-page editorial in Science dated May 18, 2001, titled: ¿Facing inheritable genetic modifications.¿ Its two authors are members of the American Association for the Advancement of Science (AAAS), which publishes Science. They serve in AAAS¿s Science and Policy Programs.

Their commentary cites opinion that this March news of inheritable genetic modification (IGM) ¿should trouble those committed to transparent public conversation about using reprogenetic¿ technologies to shape future children.¿

¿If IGM were to take hold anywhere,¿ they caution, ¿it would likely be through infertility clinics,¿ adding, ¿Web sites have already sprung up where couples can enter their preferences for height, weight, hair color, IQ, even tanning ability of egg or sperm donors in order to find just the right match.¿ They make the point that ¿the multimillion-dollar infertility industry, which is virtually unregulated, is not an environment that should be counted on to foster the safest and most responsible uses of IGM techniques.¿

The opinion piece points out that ¿IGM techniques developed for therapeutic purposes are also likely to be suitable for genetic alterations intended to improve what are already normal¿ genes.¿

The co-authors¿ take-home caveat reads: ¿Efforts to modify genes transmitted to future generations have the potential to bring about not only a medical but also a social revolution.¿

Italian Scientists Solve Two Adenoviral Vector Problems: Immunity, Intravenous Delivery Route

Up to 50 percent of adult human beings have a degree of preexisting immunity to a ubiquitous pathogen ¿ adenovirus (AV). Its rap sheet includes upper respiratory tract symptoms, pink eye, gastrointestinal infections. But neutered of its infectious replication-coding sequences, AV offers gene therapists an attractive gene-delivery vector. However, that attraction has its limitations. The widespread immunity in the population, acquired during a transient infection, downgrades AV¿s efficiency. Compounding this hang-up is administering an AV gene therapy construct by the usual route of intravenous injection. This exposes the viral vector particles to circulating neutralizing antibodies before reaching the main target organ, the liver.

Molecular biologists at La Sapienza University in Rome have successfully tested in mice a double-barreled solution to the immunity and intravenous obstacles in the path of AV gene therapies. One is the use of helper-dependent (HD) AV vectors. The other is injecting the construct into muscle rather than blood vessels.

They report their feat in the Proceedings of the National Academy of Sciences (PNAS), dated May 22, 2001. Their report is titled: ¿An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus.¿

The authors point out that ¿helper-dependent adenoviral vectors deleted of all viral coding sequences have shown an excellent gene expression profile in a variety of animal models.¿ They found that low doses of HD AV vectors achieved sustained gene expression in 100 percent of treated immunocompetent naove mice, injected intramuscularly.

¿These data,¿ they conclude, ¿suggest that human gene therapy by intramuscular delivery of helper-dependent adenoviral vectors is feasible.¿

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