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Gene expression profiling of bloodsamples could be used as a diagnosticand prognostic biomarker for the pro-gression of Huntington’s disease (HD).

Dimitri Krainc (MassGeneral Institutefor Neurodegenerative Disease andHarvard Medical School, MA, USA) andcolleagues identified genetic bio-markers in blood samples thatdistinguished patients with HD fromcontrols, and were related to diseasestage and response to treatment.

The authors also provide evidencethat such biomarkers are relevant todisease pathogenesis. A subset ofblood-marker genes were differentiallyexpressed in the brains of patientswith HD (Proc Natl Acad Sci USA 2005;102: 11023–28).

“No reliable test exists to monitordisease progression in asymptomaticcarriers of HD gene mutation”,says Krainc. “We found changes ingene expression in the blood of

presymptomatic individuals that wereassociated with progression ofdisease. Such markers of HD inpresymptomatic individuals aredesperately needed to monitor theeffects of new therapies which maydelay or prevent disease onset.”

Mutant huntingtin has been shownto interfere with the function ofwidely expressed transcription factors,suggesting that gene-expressionchanges may occur in tissue outsidethe CNS, including peripheral blood.Krainc and colleagues assessedwhether analysis of blood cells couldshow normal and abnormal biologicalprocesses in HD. The researchersidentified 322 mRNAs with alteredexpression in blood samples frompatients with HD compared withcontrols. 12 genes were chosen thatcould be used to clearly distinguishbetween patients and controls.Analysis of the concentration of each

of these marker genes in bloodsamples suggested the gene markerscould be useful during treatment formonitoring response to drugs.

“There are more than 200 newcompounds awaiting clinical trials toassess their neuroprotective propertiesin HD. The availability of biomarkersshould help in prioritising thesecompounds according to their effectson gene expression, which in turnshould greatly reduce the costs ofclinical trials”, says Krainc.

Anthony Hannan (University ofMelbourne, Australia) adds, “Suchbiomarkers should be coupled withsensitive test batteries assessing theonset of motor, cognitive andpsychiatric symptoms, so that onsetand progression can ultimately bemodelled at molecular, cellular andbehavioural levels.”

Stephanie Bartlett

602 http://neurology.thelancet.com Vol 4 October 2005

Genetic markers of Huntington’s disease discovered

Researchers have delivered genes intothe brains of living mice with anefficiency that is similar to, or betterthan, viral vectors and with noobservable toxic effect (Proc Natl AcadSci USA 2005; 102: 11539–44). Thework, undertaken by Paras Prasad(State University of New York, USA)and co-workers, provides a promisingmodel for studying the geneticmechanisms of brain disease.

Viral gene-transfer techniques candeliver a specific gene to the nucleusof a cell, for expression, throughintegration into the genome or asepisomal vectors. However, the safetyof viral vectors has been questioned,owing to the risk of excessive immuneresponse and insertional mutagenesis.

“The use of non-viral vectors,because of their non-immunogenicityand easy production, represents agood alternative to viral vectors.However, most non-viral vectors have

lacked the high transfection efficiencyobtained with viral vectors”, explainsMaja Cemazar (Institute of Oncology,Ljubljana, Slovenia).

Prasad’s team assessed theapplication of organically modifiedsilica (ORMOSIL) nanoparticles as anon-viral vector for efficient in vivogene delivery. The researchers injecteda DNA control, ORMOSIL (nanoparticlecontrol), or nanoparticles complexedwith plasmid DNA encoding thefluorescent protein EGFP (ORMOSIL/pEGFP-N2) into the substantia nigraor the lateral ventricle of mice usingstereotaxic surgery. Only injectionof ORMOSIL/pEGFP-N2 resulted inrobust EGFP expression in neuronal-like cells and EGFP transfection of cellsof the subventricular zone.

To visualise the effects in live animals,stereotaxic surgery was repeated inmice transfected with ORMOSIL/pEGFP-N2, and transfected cells were

visualised by fluorescent microscopy.The images showed a substantialpresence of transfected cells in theventricle wall. No evidence of systemicor brain-specific toxicity was shown.

“To clearly demonstrate therapeuticpotential of this novel gene deliverysystem, some other aspects need to beclarified—mainly the long-term toxicityof nanoparticles”, says Cemazar.

Prasad concludes that the results“give renewed hope to the field ofgene therapy and its practitioners,chiefly because of the demonstrationthat non-viral vectors can effectivelydeliver genes to brain cells with noneof the toxicity associated with viralvectors”. He adds: “These gene–nanoparticle complexes might make itpossible one day to actually repair theneurological damage that strokes andother brain diseases inflict.”

Laura Thomas

A non-viral vector for in vivo gene delivery