Out on the West Coast some years ago, young men in their 20s and30s started coming down with all the symptoms of Parkinson'sdisease _ muscular tremors, shuffling gait, rigid movements,droopy posture, mask-like facial expression.These are the effects brought on in the elderly with progressiveParkinson's disease, as certain brain cells, which produce theneurotransmitter dopamine, die off. The youthful victims inCalifornia were experimenting with designer drugs derived frommeperidine, a narcotic pain-killer. The careless chemistscompounding these analogs for their hallucination-seekingcustomers had put together a potent neurotoxin now known asmethyl phenyl tetrahydro pyridine (MPTP).This synthetic no-brainer does have its uses. Parkinson's diseaseresearchers create primate models of the disease by injectingmonkeys with MPTP. Such models were at the basis of thecontroversial transplantation of fetal neural tissue to replace thedopa-making cells that waste away in the brains of Parkinson'sdisease patients as they age.Now, Yale University neuroendocrinologist Matthew During isstudying a novel gene-therapy ploy in African green monkeys thathe has rendered parkinsonian by injecting them with MPTP. Histrial, still on-going, is testing an adeno-associated virus as a DNAvector encoding two enzymes that promote production of L-dopa inbrain cells.This bicistronic construct, During told BioWorld Today, containsthe genes for human tyrosine hydroxylase (TH) and aromatic aminoacid decarboyxlase. TH is an enzyme that converts the amino acidtyrosine to L-dopa. It does this indirectly, he said, by recruiting abrain neuron to synthesize a dopamine precursor. TH is lacking inthe brain cells of Parkinson's disease patients. The second enzymeconverts L-dopa to dopamine."About two and one-half months ago," During said, "we injected agroup of our severely parkinsonian monkeys intracerebrally [withthe gene-therapy construct]. It's still far too early for anyconclusions, but we do have preliminary data that looks as if we seebehavioral recovery in those primates."During added, "It looks sufficiently encouraging for us to hope thatwe could aggressively move ahead in human gene therapy ofParkinson's disease within a year or two."He explained that his approach, unlike most current efforts tomitigate the ravages of Parkinson's disease, does not aim at actuallyreversing the disease process. Rather, "we are taking neurons thatnormally wouldn't be involved in producing dopamine, andconverting them into cells producing the actual L-dopa. So it's nottrying to get the cells that are dying to make more L-dopa, or moredopamine. Instead, to take other brain cells that already have afunction and give them an additional ability to do this."It's Not A CureHe grants that this strategy "would not be curative, as Parkinson'sdisease is neither a genetic nor an enzyme-deficiency disease per se."But the ability it confers on the brain to locally synthesizedopamine "is likely to provide some significant symptomaticbenefit to Parkinson's disease patients."During and co-workers in his laboratory of molecularpharmacology at Yale have already demonstrated that this approachworks in rats. Nature Genetics for October carries their report,"Long-term gene expression and phenotypic correction usingadeno-associated virus vectors in the mammalian brain."Those experiments began by physically ablating the dopa-makingcells in one hemisphere of rats' brains to simulate Parkinson'sdisease symptoms. In rodents thus altered, this induces non-stopasymmetrical turning.Rats Show Four Months Of ImprovementDuring's gene-therapy adeno-associated virus package transferredinto rat brains only the cDNA encoding human tyrosinehydroxylase, a monocistronic construct. This preliminary trialshowed that the adeno-associated virus vector attained a creditable10 percent in vivo efficiency, expressed the human gene in the ratbrains for four months, and that the TH enzyme corrected theParkinson-like rotary movements at least partially.To administer the gene-transfer vector precisely to its target cells inthe brain requires clamping the rats' _ or monkeys' _ heads in athree-dimensional stereotactic device. This guides a fine-boreneedle through a small hole drilled in the skull to deliver theexpression vehicle to its intracerebral target."This is really a very minor surgical approach," During said;"almost, though not quite, an outpatient procedure."Adeno-associated virus is a veritable wimp among microbes. Forone thing, although it enters mammalian cells, it causes no knownillness in man or beast. For another, it can't even enter unless inclose company of an adenovirus, which does occasion mildrespiratory infection in cattle and swine.Previous gene-therapy attempts, including some of During's own,have used adenoviruses and herpes viruses as experimental gene-therapy vectors. Their total safety in humans remains a diceyquestion. During's defective adeno-associated viruses, he pointedout, are stripped of all their viral and replication sequences."We report here," his article states, "the first demonstration thatadeno-associated virus vectors can safely and stabily transfer andexpress a potentially therapeutic gene in the adult rat brain." n

-- David N. Leff Science Editor

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