By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Next to Alzheimer's disease (AD), the most prevalent neurodegenerative disorder is Parkinson's disease (PD). In lockstep with advancing age, its hallmarks are progressive tremor, rigidity and slowed body movements.
Unlike AD, the proximate cause of PD is known. The ailment arises from the death of neurons in the brain that secrete dopamine, a potent multipurpose molecule. The specific chemotherapy for PD is L-dopa, a precursor drug that stimulates dopamine production. But L-dopa's effectiveness dwindles with its prolonged use.
It is degeneration of the brain's substantia nigra that leads to the loss of dopaminergic neurons in the striatum. This process can be - and is being - reversed or halted by intracranial transplants of human embryonic brainstem tissue. This heroic, albeit still experimental, intervention has proved so successful clinically that many of its recipients have been able to kick their L-dopa habit.
But there are at least two deal-breaking downsides to this apparent fix for PD, one socio-political, the other practical. The first turns on the ethical objections raised, largely by the right-to-life movement, and parallel legislative bans on the use of human fetal tissues.
The technical hitch reflects the fact that only 5 percent to 20 percent of those embryonic dopamine neurons survive for any useful length of time in vivo. Hence, reactivating the neurons on both sides of a PD patient's brain requires transplanting tissue from six to eight donor embryos.
One way around this roadblock, now under active study, is xenotransplantation - using tissue from compatible animal sources, notably, pig brains. However, the first attempts at porcine xenografts into PD patients resulted in poor survival of dopamine-producing neurons, and consequently equivocal clinical results.
Meanwhile, multipotent neural stem cells are emerging of late as a potentially unlimited source of dopaminergic neurons. Molecular neurobiologists at Sweden's Karolinska Institute in Stockholm have taken two giant steps along this new path. Their progress report, in the July 1999 issue of Nature Biotechnology, bears the title: "Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes."
A co-author of their paper is pediatric neurologist Evan Snyder, at Harvard Medical School in Boston. A long-time collaborator of the Swedish group, Snyder contributed the neural stem cells (NSCs) to their just-reported experiments. (See BioWorld Today, June 8, 1999, p. 1.)
"I knew that these NSCs of ours can easily become neurons," Snyder told BioWorld Today. "The question was: How to make them dopaminergic?" The answer is contained in two key components - the Nurr1 gene and the type 1 astrocytes - embedded in their paper's title.
Nurr1 encodes a transcription factor responsible for inducing and maintaining midbrain dopamine neurons. Its overexpression caused newborn cells to opt for becoming neurons. But they didn't secrete any dopamine until treated with cultured rat midbrain cells and basic fibroblast growth factor. The co-authors then determined, in extensive in vitro experiments, that the neuronal signal essential to the dopaminergic effect was switched on by non- neuronal brain cells, the astrocytes, or neuroglia.
But not just any astrocytes would do that job, they found. Those cells had to come from the rats' midbrain region, and be co-cultured with the Nurr1 protein. The team surgically injected these cells into the corpus striatum of adult mice, and allowed them to mature for 12 days. "Although many cells were lost in this condition," their paper reported, "a few of [these] dopaminergic cells displayed a high level of differentiation and apparent integration into the host tissue."
It concluded, "The induction of an unlimited number of midbrain dopaminergic neurons in vitro, that can engraft in vivo, could prove particularly useful in cell replacement strategies to treat Parkinson's disease."
Harvard's Snyder presumes that his Swedish colleagues "are right now in the midst of the therapeutic direction of actually putting murine cells into rat or mouse models of PD." As for eventual human trials, he observed, "The first major point is to show that this exact technique can work for human neural stem cells. And if that turns out to be the case, then one could make a very compelling argument for using these in the transplant studies that are actively going on now in PD patients. Just being able to supply a cell in which you have better control than in fetal tissue," Snyder concluded, "may be very appealing, and probably would get permission fairly quickly to go to clinical trials."
New Anti-HIV Drug Breaks AIDS Treatment Affordability Barrier In NIAID/Ugandan Trial
In the underdeveloped countries of the world, 1,800 babies are born every day infected with the AIDS virus. They join the millions of HIV-positive people who represent 95 percent of the worldwide AIDS-threatened population. The other 5 percent, in the industrialized nations, can afford the cocktail of antiretroviral and protease drugs, including AZT, that have made striking inroads on the disease in the past few years.
Last Wednesday, by Telstar 6 satellite downlink, the National Institute of Allergy and Infectious Diseases reported heartening interim results of a new joint program with health workers in Uganda to spare infants born to HIV-infected mothers from inheriting the virus. It consists of giving a single oral dose of a new non-nucleoside reverse transcriptase inhibitor drug, nevirapine, to pregnant mothers in labor, and a second one to her child within three days of birth. At 14 to 16 weeks of age, 13.1 percent of newborns who received nevirapine were infected with HIV, compared to 25.1 percent of those in an AZT control group."
"If implemented widely in developing countries," the NIAID release stated, "it could prevent some 300,000 to 400,000 newborns per year from beginning life with HIV. In parts of subSaharan Africa," it pointed out, "up to 30 percent of pregnant women are infected with HIV, and 25 to 35 percent of their infants will be born infected." It noted, "The cost of the drug used in the nevirapine regimen is approximately 200 times cheaper than the long-course AZT used in the U.S."