By David N. Leff
Editor's note: Science Scan is a round-up of recently published biotechnology-related research — in this instance, a random sampling of presentations at last week's 27th annual meeting, in New Orleans, of the Society for Neuroscience.
Adenoviral vectors inserted genes encoding the Neuronal Apoptosis Inhibitory Factor (NAIP) into the dopamine-producing neurons of rat brains. One week later, the animals received intracerebral injections of 6-OHDA, a nerve toxin that destroys such neurons, thus simulating the progression of Parkinson's disease (PD).
In behavioral testing three weeks later, the rats displayed "substantially decreased behavioral impairments," compared to controls. This finding, which suggested that NAIP had increased dopaminergic-neuron survival, was subsequently confirmed by cell counts.
"We have demonstrated," said neuroscientist George Robertson, "that increasing the expression of the NAIP protein can protect brain cells by inhibiting the brain cell death associated with PD. Robertson is an associate professor of cellular and molecular medicine at the University of Ottawa, and director of the neuroprotection program at Ottawa-based Apoptogen Inc. (See BioWorld Today, Sept. 3, 1997, p. 1.)
Somatix's Site-Specific Gene Therapy Adds Dopamine To PD Rats' Brains, Regulates Its Output By Oral L-Dopa
Neuroscientists at Somatix Therapy Corp., of Alameda, Calif., reported somewhat similar gene therapy trials, employing an adeno-associated viral vector and a different gene. Their approach expressed the human enzyme, l-aromatic amino acid decarboxylase, to the forebrains of 16 rats. This enzyme converts the anti-parkinsonian levodopa (L-dopa) to dopamine.
After the striatum-targeted gene therapy, the rats converted more levodopa to dopamine than did otherwise identical control animals. "In additional preclinical studies following the gene therapy treatment," said Somatix scientist Ron Mandel, "we demonstrated that the human enzyme was being made in neurons, and was active in those rats' brains."
Moreover, he added, "That enzyme becomes functional only in the presence of L-dopa. Therefore, oral administration of L-dopa provides a straightforward gene regulation system that could enable customized dosing, and minimize side effects."
Neurex Reports 'New Class Of Brain, Neurological Therapeutics,' Derived From African Tarantula Toxin
In a presentation titled "A Selective Antagonist of R-type calcium channels, from the venom of the African tarantula, Hysterocrates gigas," George Miljanich, senior research director at Neurex Corp., Menlo Park, Calif., introduced the firm's newest nerve compound, SNX-482.
This Cameroon Red Tarantula toxin derivative joins the putative pain-controlling product, SNX-111, isolated by Neurex scientists two years ago from Conus magus, the cone snail. Its venom is reputedly the deadliest known. (See BioWorld Today, Nov. 14, 1995, p. 1.)
SNX-111 acts on the N-type calcium channel blocker; SNX-482 on the more mysterious R-channel. It's thought to play an important role in the body's neural communication network," Miljanich said, "where it contributes to the regulation of brain function. Initial experiments in animal models," he added, "have already suggested ways in which this class of compounds may be therapeutically useful."
NIA Unveils Phenserine, A New Alzheimer's Disease Drug That Improved Memory, Cognition, In Animals
A novel memory booster for treating Alzheimer's disease (AD) has passed its preclinical tests at the National Institute of Aging (NIA), and is poised for human trials. NIA co-developer Nigel Greig presented the compound, phenserine, as an "exciting new anticholinesterase and cognitive enhancer" that "dramatically improved memory and slowed the AD progression in rat and canine animal models."
Phenserine acts by restoring levels of acetylcholine, a neurotransmitter critical to memory and cognition, which is lost in AD. It also lowers the amount of beta-amyloid precursor protein produced in memory-specific, AD-sensitive brain regions.
"The preclinical in vivo experiments found phenserine free," Greig reported, "of the hepatoc toxicity associated with tacrine (Cognex), one of the only two drugs approved in the U.S. for the treatment of AD." The other is E2020 (Aricept).
Acetylcholine is broken down in the brain by acetylcholinesterase, the enzyme targeted for destruction by phenserine. Cognex and Aricept do the same job, but less selectively and reversibly. "In this way," Greig observed, "phenserine overcomes one of the major problems of current AD therapeutics, the ability to deliver sufficient drug to the brain without producing debilitating side effects." And it does it with a once-a-day dose.
Microprocessor-Controlled Precision Injection Of Vectors Into Mouse Brains Beat Out Manual Method
The quickness of a magician's hand may deceive the eye, but hands have certain shortcomings. When it comes to manually delivering vectors to brain targets in rats, gene therapists wish there were a better way.
An unpublished answer to this prayer got its first exposure at the Neuroscience meeting, presented by its co-inventor, Andrew Brooks, of the University of Rochester, New York. He described the device as "a reproducible and efficient murine CNS [central nervous system] gene delivery system, using a microprocessor-controlled injector."
The apparatus consists of a stereotaxic-mounted pump that inserts the vehicle containing the vector and a microprocessor-based controller, which programs volume, rate and syringe size.
"Unlike the manual method," Brooks pointed out, "where brain injections lead to considerable spread of the masterial being injected, the microprocessor system restricts gene expression to the areas of interest."
He added: "When tested using a variety of gene transfer vehicles, including herpes amplicon virus, adenovirus, synthetic cationic lipids and naked DNA, the microprocessor method significantly increased gene expression levels," he reported, as demonstrated in multiple mouse comparative experiments. *